Macrocyclic proline derived hcv serine protease inhibitors

ABSTRACT

The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof: 
     
       
         
         
             
             
         
       
     
     which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

RELATED APPLICATIONS

This application is a is a continuation application of U.S. applicationSer. No. 16/142,087, filed on Sep. 26, 2018, which is a continuationapplication of U.S. application Ser. No. 15/839,249, filed Dec. 12,2017, now abandoned, which is a continuation application of U.S.application Ser. No. 15/287,042, filed on Oct. 6, 2016, now abandoned,which is a continuation application of U.S. application Ser. No.14/946,866, filed Nov. 20, 2015, now abandoned, which is a continuationapplication of U.S. application Ser. No. 14/146,161, filed Jan. 2, 2014,now U.S. Pat. No. 9,220,748, issued on Dec. 29, 2015, which is acontinuation application of U.S. application Ser. No. 13/237,120, filedon Sep. 20, 2011, now U.S. Pat. No. 8,648,037, issued on Feb. 11, 2014,which claims the benefit of U.S. Provisional Application No. 61/385,058,filed on Sep. 21, 2010, U.S. Provisional Application No. 61/499,994,filed on Jun. 22, 2011, and U.S. Provisional Application No. 61/504,616,filed on Jul. 5, 2011. The entire teachings of the above applicationsare incorporated herein by reference.

JOINT RESEARCH AGREEMENT

Inventions described in this application were made by or on behalf ofEnanta Pharmaceuticals, Inc. and Abbott Laboratories who are parties toa joint research agreement, that was in effect on or before the datesuch inventions were made and such inventions were made as a result ofactivities undertaken within the scope of the joint research agreement.

TECHNICAL FIELD

The present invention relates to novel hepatitis C virus (HCV) proteaseinhibitor compounds, methods for using the same to treat HCV infection,as well as processes for making such compounds.

BACKGROUND OF THE INVENTION

HCV is the principal cause of non-A, non-B hepatitis and is anincreasingly severe public health problem both in the developed anddeveloping world. It is estimated that the virus infects over 200million people worldwide, surpassing the number of individuals infectedwith the human immunodeficiency virus (HIV) by nearly five fold. HCVinfected patients, due to the high percentage of individuals inflictedwith chronic infections, are at an elevated risk of developing cirrhosisof the liver, subsequent hepatocellular carcinoma and terminal liverdisease. HCV is the most prevalent cause of hepatocellular cancer andcause of patients requiring liver transplantations in the western world.

There are considerable barriers to the development of anti-HCVtherapeutics, which include, but are not limited to, the persistence ofthe virus, the genetic diversity of the virus during replication in thehost, the high incident rate of the virus developing drug-resistantmutants, and the lack of reproducible infectious culture systems andsmall-animal models for HCV replication and pathogenesis. In a majorityof cases, given the mild course of the infection and the complex biologyof the liver, careful consideration must be given to antiviral drugs,which are likely to have significant side effects.

Only two approved therapies for HCV infection are currently available.The original treatment regimen generally involves a 3-12 month course ofintravenous interferon-α (IFN-α), while a new approved second-generationtreatment involves co-treatment with IFN-α and the general antiviralnucleoside mimics like ribavirin. Both of these treatments suffer frominterferon related side effects as well as low efficacy against HCVinfections. There exists a need for the development of effectiveantiviral agents for treatment of HCV infection due to the poortolerability and disappointing efficacy of existing therapies.

In a patient population where the majority of individuals arechronically infected and asymptomatic and the prognoses are unknown, aneffective drug would desirably possess significantly fewer side effectsthan the currently available treatments. The hepatitis C non-structuralprotein-3 (NS3) is a proteolytic enzyme required for processing of theviral polyprotein and consequently viral replication. Despite the hugenumber of viral variants associated with HCV infection, the active siteof the NS3 protease remains highly conserved thus making its inhibitionan attractive mode of intervention. Recent success in the treatment ofHIV with protease inhibitors supports the concept that the inhibition ofNS3 is a key target in the battle against HCV.

HCV is a flaviridae type RNA virus. The HCV genome is enveloped andcontains a single strand RNA molecule composed of circa 9600 base pairs.It encodes a polypeptide comprised of approximately 3010 amino acids.

The HCV polyprotein is processed by viral and host peptidase into 10discreet peptides which serve a variety of functions. There are threestructural proteins, C, E1 and E2. The P7 protein is of unknown functionand is comprised of a highly variable sequence. There are sixnon-structural proteins. NS2 is a zinc-dependent metalloproteinase thatfunctions in conjunction with a portion of the NS3 protein. NS3incorporates two catalytic functions (separate from its association withNS2): a serine protease at the N-terminal end, which requires NS4A as acofactor, and an ATP-ase-dependent helicase function at the carboxylterminus. NS4A is a tightly associated but non-covalent cofactor of theserine protease.

The NS3/4A protease is responsible for cleaving four sites on the viralpolyprotein. The NS3-NS4A cleavage is autocatalytic, occurring in cis.The remaining three hydrolyses, NS4A-NS4B, NS4B-NS5A and NS5A-NS5B alloccur in trans. NS3 is a serine protease which is structurallyclassified as a chymotrypsin-like protease. While the NS serine proteasepossesses proteolytic activity by itself, the HCV protease enzyme is notan efficient enzyme in terms of catalyzing polyprotein cleavage. It hasbeen shown that a central hydrophobic region of the NS4A protein isrequired for this enhancement. The complex formation of the NS3 proteinwith NS4A seems necessary to the processing events, enhancing theproteolytic efficacy at all of the sites.

A general strategy for the development of antiviral agents is toinactivate virally encoded enzymes, including NS3, that are essentialfor the replication of the virus. Current efforts directed toward thediscovery of NS3 protease inhibitors were reviewed by S. Tan, A. Pause,Y. Shi, N. Sonenberg, Hepatitis C Therapeutics: Current Status andEmerging Strategies, Nature Rev. Drug Discov. 1, 867-881 (2002).

SUMMARY OF THE INVENTION

In one aspect, the invention provides compounds represented by FormulaI, or pharmaceutically acceptable salts, esters, or prodrugs thereof:

wherein:

A is absent, —(C═O)—, —S(O)₂—, —C(═N—OR₁)— or —C(═N—CN)—;

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;or

wherein R₇ and R₈ are each independently C₁-C₈ alkyl or C₂-C₈ alkenyland are each independently optionally substituted with one or more halo;

-   -   M₁ and M₂ are each independently selected from O and NR₁;    -   each R₁ is independently selected at each occurrence from the        group consisting of:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl; substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   L₁ and L₂ are each independently selected from —C₁-C₈ alkylene,        —C₂-C₈ alkenylene, or —C₂-C₈ alkynylene each containing 0, 1, 2,        or 3 heteroatoms selected from O, S, or N; substituted —C₁-C₈        alkylene, substituted —C₂-C₈ alkenylene, or substituted —C₂-C₈        alkynylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂        cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkenylene, or substituted —C₃-C₁₂        cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms        selected from O, S or N;    -   W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;    -   X and Y, taken together with the carbon atoms to which they are        attached, form a cyclic moiety selected from aryl, substituted        aryl, heteroaryl, substituted heteroaryl, heterocyclic,        substituted heterocylic, carbocyclic and substituted        carbocyclic;    -   X′ is N or —C(R₂)—, where R₂ is selected from the group        consisting of:    -   (i) hydrogen, halogen, CN, CF₃, NO₂, OR₃, SR₃, —NHS(O)₂—R₃,        —NH(SO₂)NR₄R₅, NR₄R₅, CO₂R₃, COR₃, CONR₄R₅, N(R₁)COR₃; aryl;        substituted aryl; heteroaryl; or substituted heteroaryl;    -   (ii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   each R₃ is independently selected from C₁-C₈ alkyl, —C₂-C₈        alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N, substituted —C₁-C₈ alkyl,        substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;        and —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, or substituted —C₃-C₁₂ cycloalkenyl; heterocylic;        substituted heterocyclic; aryl; substituted aryl; heteroaryl; or        substituted heteroaryl;    -   each R₄ and R₅ are independently selected from H and R₃, or R₄        and R₅ together with the nitrogen atom to which they are        attached form a heterocyclic ring;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen or deuterium;    -   G is selected from —OH, —NHS(O)₂—R₃, —NH(SO₂)NR₄R₅, and NR₄R₅;        and    -   R″ is selected from hydrogen, methyl, ethyl, and allyl.

In one embodiment,

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl.

In one embodiment of the invention,

is selected from, but not limited to, the group of rings consisting of:

Preferably, X and Y, taken together with the carbon atoms to which theyare attached, form a cyclic moiety selected from aryl, substituted aryl,heteroaryl, substituted heteroaryl, heterocyclic and substitutedheterocylic, more preferably aryl, substituted aryl, heteroaryl orsubstituted heteroaryl. Most preferably, X and Y, taken together withthe carbon atoms to which they are attached, form a benzo or substitutedbenzo ring.

In another embodiment, the present invention features pharmaceuticalcompositions comprising a compound of the invention (e.g., Formula I),or a pharmaceutically acceptable salt, ester or prodrug thereof. Instill another embodiment of the present invention there are disclosedpharmaceutical compositions comprising a therapeutically effectiveamount of a compound of the invention (e.g., Formula I), or apharmaceutically acceptable salt, ester or prodrug thereof, incombination with a pharmaceutically acceptable carrier or excipient. Inyet another embodiment of the invention are methods of treating ahepatitis C infection in a subject in need of such treatment with saidcompound of the invention (e.g., Formula I), or said pharmaceuticalcompositions.

Other features, objects, and advantages of the present invention areapparent in the detailed description that follows. It should beunderstood, however, that the detailed description, while indicatingpreferred embodiments of the invention, are given by way of illustrationonly, not limitation. Various changes and modifications within the scopeof the invention will become apparent to those skilled in the art fromthe detailed description.

DETAILED DESCRIPTION OF THE INVENTION

A first embodiment of the invention is a compound represented by FormulaI as described above, or a pharmaceutically acceptable salt, ester orprodrug thereof, alone or in combination with a pharmaceuticallyacceptable carrier or excipient.

Another embodiment of the invention is a compound represented by FormulaII:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where X₁-X₄ are independently selected from —CR₆ and N,wherein each R₆ is independently selected from:

-   -   (i) hydrogen; halogen; —NO₂; —CN; or N₃;    -   (ii) -M-R₃, wherein M is O, S, or NH;    -   (iii) NR₄R₅;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   (v) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl; and    -   (vi) heterocycloalkyl or substituted heterocycloalkyl;

A is absent, —(C═O)—, —S(O)₂—, —C(═N—OR₁)— or —C(═N—CN)—;

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

-   -   or

wherein R₇ and R₈ are each independently C₁-C₈ alkyl or C₂-C₈ alkenyland are each independently optionally substituted with one or more halo;

-   -   M₁ and M₂ are each independently selected from O and NR₁;    -   each R₁ is independently selected at each occurrence from the        group consisting of:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   L₁ and L₂ are each independently selected from —C₁-C₈ alkylene,        —C₂-C₈ alkenylene, or —C₂-C₈ alkynylene each containing 0, 1, 2,        or 3 heteroatoms selected from O, S, or N; substituted —C₁-C₈        alkylene, substituted —C₂-C₈ alkenylene, or substituted —C₂-C₈        alkynylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂        cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkenylene or substituted —C₃-C₁₂        cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms        selected from O, S or N;    -   W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;    -   X′ is N or —C(R₂)—, where R₂ is selected from the group        consisting of:    -   (i) hydrogen, halogen, CN, CF₃, NO₂, OR₃, SR₃, —NHS(O)₂—R₃,        —NH(SO₂)NR₄R₅, NR₄R₅, CO₂R₃, COR₃, CONR₄R₅, N(R₁)COR₃; aryl;        substituted aryl; heteroaryl; or substituted heteroaryl;    -   (ii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   each R₃ is independently selected from C₁-C₈ alkyl, —C₂-C₈        alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N, substituted —C₁-C₈ alkyl,        substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;        —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; heterocylic;        substituted heterocyclic; aryl; substituted aryl; heteroaryl;        and substituted heteroaryl;    -   each R₄ and R₅ are independently selected from H and R₃, or R₄        and R₅ combined together with the N they are attached to form a        heterocyclic ring;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen; deuterium;    -   G is selected from —OH, —NHS(O)₂—R₃, —NH(SO₂)NR₄R₅, and NR₄R₅;        and    -   R″ is selected from hydrogen, methyl, ethyl, and allyl.

Another embodiment of the invention is a compound represented by FormulaIII or IV:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, where each Y₁ and Y₂ are independently selected from CR₆ andN, and each Y₃ is independently selected from NR₆, S and O;

each R₆ is independently selected from:

-   -   (i) hydrogen; halogen; —NO₂; —CN; or N₃;    -   (ii) -M-R₃, wherein M is O, S, or NH;    -   (iii) NR₄R₅;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   (v) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl; and    -   (vi) heterocycloalkyl or substituted heterocycloalkyl;

A is absent, —(C═O)—, —S(O)₂—, —C(═N—OR₁)— or —C(═N—CN)—;

_is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

-   -   or

wherein R₇ and R₈ are each independently C₁-C₈ alkyl or C₂-C₈ alkenyland are each independently optionally substituted with one or more halo;

-   -   M₁ and M₂ are each independently selected from O and NR₁;    -   each R₁ is independently selected at each occurrence from the        group consisting of:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   L₁ and L₂ are each independently selected from —C₁-C₈ alkylene,        —C₂-C₈ alkenylene, or —C₂-C₈ alkynylene each containing 0, 1, 2,        or 3 heteroatoms selected from O, S, or N; substituted —C₁-C₈        alkylene, substituted —C₂-C₈ alkenylene, or substituted —C₂-C₈        alkynylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkylene, or substituted —C₃-C₁₂        cycloalkylene each containing 0, 1, 2, or 3 heteroatoms selected        from O, S or N; —C₃-C₁₂ cycloalkenylene, or substituted —C₃-C₁₂        cycloalkenylene each containing 0, 1, 2, or 3 heteroatoms        selected from O, S or N;    -   W is absent, —O—, —S—, —NH—, —N(Me)-, —C(O)NH—, or —C(O)N(Me)-;    -   X′ is N or —C(R₂)—, where R₂ is selected from the group        consisting of:    -   (i) hydrogen, halogen, CN, CF₃, NO₂, OR₃, SR₃, —NHS(O)₂—R₃,        —NH(SO₂)NR₄R₅, NR₄R₅, CO₂R₃, COR₃, CONR₄R₅, N(R₁)COR₃; aryl;        substituted aryl; heteroaryl; or substituted heteroaryl;    -   (ii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   each R₃ is independently selected from C₁-C₈ alkyl, —C₂-C₈        alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N, substituted —C₁-C₈ alkyl,        substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;        —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; heterocylic;        substituted heterocyclic; aryl; substituted aryl; heteroaryl;        and substituted heteroaryl;    -   each R₄ and R₅ are independently selected from H and R₃, or R₄        and R₅ combined together with the N they are attached to form a        heterocyclic ring;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen or deuterium;    -   G is selected from —OH, —NHS(O)₂—R₃, —NH(SO₂)NR₄R₅, and NR₄R₅;        and    -   R″ is selected from hydrogen, methyl, ethyl, and allyl.

Another embodiment of the invention is a compound represented by FormulaV:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, wherein

X₁-X₄ are independently selected from —CR₆ and N, wherein each R₆ isindependently selected from:

-   -   (i) hydrogen; halogen; —NO₂; —CN; or N₃;    -   (ii) -M-R₃, where M is O, S, or NH;    -   (iii) NR₄R₅;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   (v) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl; and    -   (vi) heterocycloalkyl or substituted heterocycloalkyl;

A is absent, —(C═O)—, —S(O)₂—, —C(═N—OR₁)— or —C(═N—CN)—;

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

-   -   or

wherein R₇ and R₈ are each independently C₁-C₈ alkyl or C₂-C₈ alkenyland are each independently optionally substituted with one or more halo;

-   -   M₁ and M₂ are each independently selected from O and NR₁;    -   each R₁ is independently selected at each occurrence from the        group consisting of:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   X′ is N or —C(R₂)—, where R₂ is selected from the group        consisting of:    -   (i) hydrogen, halogen, CN, CF₃, NO₂, OR₃, SR₃, —NHS(O)₂—R₃,        —NH(SO₂)NR₄R₅, NR₄R₅, CO₂R₃, COR₃, CONR₄R₅, N(R₁)COR₃; aryl;        substituted aryl; heteroaryl; or substituted heteroaryl;    -   (ii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   each R₃ is independently selected from C₁-C₈ alkyl, —C₂-C₈        alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N, substituted —C₁-C₈ alkyl,        substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;        —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; heterocylic;        substituted heterocyclic; aryl; substituted aryl; heteroaryl;        and substituted heteroaryl;    -   each R₄ and R₅ are independently selected from H and R₃, or R₄        and R₅ combined together with the N they are attached to form a        heterocyclic ring;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen; or deuterium;    -   G is selected from —OH, —NHS(O)₂—R₃, —NH(SO₂)NR₄R₅, and NR₄R₅;        and    -   R″ is selected from hydrogen, methyl, ethyl, and allyl.

Another embodiment of the invention is a compound represented by FormulaVI:

or a pharmaceutically acceptable salt, ester or prodrug thereof, aloneor in combination with a pharmaceutically acceptable carrier orexcipient, wherein:

X₁-X₄ are independently selected from —CR₆ and N, wherein each R₆ isindependently selected from:

-   -   (i) hydrogen; halogen; —NO₂; —CN; or N₃;    -   (ii) -M-R₃, wherein M is O, S, or NH;    -   (iii) NR₄R₅;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   (v) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl; and    -   (vi) heterocycloalkyl or substituted heterocycloalkyl;

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

-   -   or

wherein R₇ and R₈ are each independently C₁-C₈ alkyl or C₂-C₈ alkenyland are each independently optionally substituted with one or more halo;

-   -   M₁ and M₂ are each independently selected from O and NR₁;    -   each R₁ is independently selected at each occurrence from the        group consisting of:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   each R₃ is independently selected from C₁-C₈ alkyl, —C₂-C₈        alkenyl, or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N, substituted —C₁-C₈ alkyl,        substituted —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;        —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; heterocylic;        substituted heterocyclic; aryl; substituted aryl; heteroaryl;        and substituted heteroaryl;    -   each R₄ and R₅ are independently selected from H and R₃, or R₄        and R₅ combined together with the N they are attached to form a        heterocyclic ring;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen; or deuterium;    -   G is selected from —OH, —NHS(O)₂—R₃, —NH(SO₂)NR₄R₅, and NR₄R₅;        and    -   R″ is selected from hydrogen, methyl, ethyl, and allyl.

The present invention also features compounds of Formula VII andpharmaceutically acceptable salts, esters, and prodrugs thereof:

wherein R^(1′), R^(2′), R^(3′) and R^(4′) are each independently R₆, orR′ and R^(2′), R^(2′) and R^(3′), or R^(3′) and R^(4′) taken togetherwith the carbon atoms to which each is attached, form an aromatic,heteroaromatic, cyclic or heterocyclic ring;

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

-   -   or

wherein R₇ and R₈ are each independently C₁-C₈ alkyl or C₂-C₈ alkenyland are each independently optionally substituted with one or more halo;

-   -   each R₆ is independently selected from:    -   (i) hydrogen; halogen; —NO₂; —CN; or N₃;    -   (ii) -M-R₃, wherein M is O, S, or NH;    -   (iii) NR₄R₅;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   (v) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl; and    -   (vi) heterocycloalkyl or substituted heterocycloalkyl;    -   R₃ is independently selected from C₁-C₈ alkyl, —C₂-C₈ alkenyl,        or —C₂-C₈ alkynyl each containing 0, 1, 2, or 3 heteroatoms        selected from O, S or N, substituted —C₁-C₈ alkyl, substituted        —C₂-C₈ alkenyl, or substituted —C₂-C₈ alkynyl each containing 0,        1, 2, or 3 heteroatoms selected from O, S or N; —C₃-C₁₂        cycloalkyl, substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂        cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; heterocylic;        substituted heterocyclic; aryl; substituted aryl; heteroaryl;        and substituted heteroaryl;    -   each R₄ and R₅ are independently selected from H and R₃, or R₄        and R₅ combined together with the N they are attached to form a        heterocyclic ring;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl,        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl,        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl,        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; or substituted        heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen; or deuterium;    -   R″ is selected from hydrogen, methyl, ethyl, and allyl.

In certain embodiments of the compounds of Formulas I-VII,

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

In certain embodiments,

in Formulas I-VII is C₃-C₁₂ carbocycle or 4- to 6-membered heterocycleand is optionally substituted with one or more substituentsindependently selected from halo, C₁-C₈ alkyl or C₂-C₈ alkenyl. Forinstance,

can be a non-aromatic C₃-C₆ carbocycle or a non-aromatic 4- to6-membered heterocycle and is optionally substituted with one or moresubstituents independently selected from halo, C₁-C₆ alkyl or C₂-C₆alkenyl. More preferably,

is saturated C₄-C₆ carbocycle or saturated 4- to 6-membered heterocycleand is optionally substituted with one or more substituentsindependently selected from halo, C₁-C₈ alkyl or C₂-C₈ alkenyl.

In certain embodiments of the compounds of Formulas I to VII,

is selected from the group consisting of:

Highly preferably,

is selected from the group below:

Preferably, R^(1′), R^(2′), R^(3′) and R^(4′) are hydrogen. Alsopreferably, R^(1′) and R^(4′) are hydrogen; and one of R^(2′) and R^(3′)is hydrogen, and the other is selected from halo, methyl optionallysubstituted with one or more halo, or —O-methyl optionally substitutedwith one or more halo.

Also, preferably R^(1′) and R^(2′), or R^(2′) and R^(3′), or R^(3′) andR^(4′), taken together with the carbon atoms to which they are attached,form a 5- or 6-membered carbocycle or heterocycle (e.g., phenyl), andthe rest of R^(1′), R^(2′), R^(3′) and R^(4′) preferably are hydrogen.

Preferably, R₃ is

Preferably, R′ is

more preferably

Preferably, R is

more preferably

In one embodiment, the present invention features compounds of FormulaVII or pharmaceutically acceptable salts thereof, wherein

R′ is vinyl

or difluoromethyl

R₃ is

and R is

In another embodiment, the present invention features compounds ofFormula VII or pharmaceutically acceptable salts thereof, wherein

R′ is vinyl

or difluoromethyl

R₃ is

and R is

R^(3′) is —O-methyl optionally substituted with one or more halo, andR^(1′), R^(2′), and R^(4′) are hydrogen.

In yet another embodiment, the present invention features compounds ofFormula VII or pharmaceutically acceptable salts thereof, wherein

R′ is vinyl

or difluoromethyl

R₃ is

and R is

and R, R^(2′), R^(3′) and R^(4′) are hydrogen.

In another embodiment, the present invention features compounds ofFormula VII or pharmaceutically acceptable salts thereof, wherein

R′ is vinyl

or difluoromethyl

R₃ is

and R is

R^(3′) is halo (e.g, F), and R^(1′), R^(2′), and R^(4′) are hydrogen.

In still another embodiment, the present invention features compounds ofFormula VII or pharmaceutically acceptable salts thereof, wherein

R′ is vinyl

or difluoromethyl

R₃ is

and R is

R^(3′) and R^(4′) taken together with carbon atoms to which they areattached form phenyl, and R′ and R^(2′) are hydrogen.

In another aspect, the invention provides a compound of Formula VIII:

wherein:

A is absent, or selected from —(C═O)—, —S(O)₂—, —C(═N—OR₁)— and—C(═N—CN)—;

is selected from —C₃-C₁₂ cycloalkyl, substituted —C₃-C₁₂ cycloalkyl;—C₃-C₁₂ cycloalkenyl, substituted —C₃-C₁₂ cycloalkenyl; —C₃-C₁₂heterocycloalkyl, and substituted —C₃-C₁₂ heterocycloalkyl;

-   -   M₁ and M₂ are selected from O and NR₁; wherein R₁ is selected at        each occurrence from the group consisting of:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms independently selected from        O, S and N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈        alkenyl, or substituted —C₂-C₈ alkynyl each containing 0, 1, 2,        or 3 heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   L₁ and L₂ are independently selected from —C₁-C₈ alkylene,        —C₂-C₈ alkenylene, or —C₂-C₈ alkynylene each containing 0, 1, 2,        or 3 heteroatoms independently selected from O, S and N;        substituted —C₁-C₈ alkylene, substituted —C₂-C₈ alkenylene, or        substituted —C₂-C₈ alkynylene each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkylene, or        substituted —C₃-C₁₂ cycloalkylene each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkenylene, or        substituted —C₃-C₁₂ cycloalkenylene each containing 0, 1, 2, or        3 heteroatoms selected from O, S or N;    -   W is absent, or selected from —O—, —S—, —NH—, —N(Me)-, —C(O)NH—,        and —C(O)N(Me)-;    -   X and Y, taken together with the carbon atoms to which they are        attached, form a cyclic moiety selected from aryl, substituted        aryl, heteroaryl, substituted heteroaryl, heterocyclic, and        substituted heterocylic;    -   X′ is selected from N and —C(R₂)—, where R₂ is selected from the        group consisting of:    -   (i) hydrogen, halogen, CN, CF₃, NO₂, OR₁, SR₁, —NHS(O)₂—R₂,        —NH(SO₂)NR₃R₄, NR₃R₄, CO₂R₁, COR₁, CONR₁R₂, N(R₁)COR₂;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms independently selected from        O, S and N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈        alkenyl, or substituted —C₂-C₈ alkynyl each containing 0, 1, 2,        or 3 heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl;    -   R and R′ are each independently selected from the group        consisting of:    -   (i) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms independently selected from        O, S and N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈        alkenyl, or substituted —C₂-C₈ alkynyl each containing 0, 1, 2,        or 3 heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂ cycloalkyl; —C₄-C₁₂ alkylcycloalkyl, or        substituted —C₄-C₁₂ alkylcycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl; —C₄-C₁₂ alkylcycloalkenyl, or        substituted —C₄-C₁₂ alkylcycloalkenyl;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl; and    -   (iv) hydrogen; deuterium;    -   G is selected from —OH, —NHS(O)₂—R₃, —NH(SO₂)NR₄R₅, and NR₄R₅;    -   R₃ is selected from:    -   (i) aryl; substituted aryl; heteroaryl; substituted heteroaryl    -   (ii) heterocycloalkyl; substituted heterocycloalkyl; and    -   (iii) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms selected from O, S or N,        substituted —C₁-C₈ alkyl, substituted —C₂-C₈ alkenyl, or        substituted —C₂-C₈ alkynyl each containing 0, 1, 2, or 3        heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂ cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl; heterocylic; substituted        heterocyclic;    -   R₄ and R₅ are independently selected from:    -   (i) hydrogen;    -   (ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;    -   (iii) heterocycloalkyl or substituted heterocycloalkyl;    -   (iv) —C₁-C₈ alkyl, —C₂-C₈ alkenyl, or —C₂-C₈ alkynyl each        containing 0, 1, 2, or 3 heteroatoms independently selected from        O, S and N; substituted —C₁-C₈ alkyl, substituted —C₂-C₈        alkenyl, or substituted —C₂-C₈ alkynyl each containing 0, 1, 2,        or 3 heteroatoms selected from O, S or N; —C₃-C₁₂ cycloalkyl, or        substituted —C₃-C₁₂cycloalkyl; —C₃-C₁₂ cycloalkenyl, or        substituted —C₃-C₁₂ cycloalkenyl; heterocyclic, or substituted        heterocyclic;

and

-   -   R″ is selected from hydrogen, methyl, ethyl and allyl.

Representative compounds of the invention include, but are not limitedto, the following compounds (example 1 to example 256 in Table 1)according to Formula VIII wherein R, -L₂-W-L₁-,

R′ and G are delineated for each example in Table 1.

TABLE 1 Example # R —L₂—W—L₁—

R′ G 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

152.

153.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

168.

169.

170.

171.

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184.

185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

197.

198.

199.

200.

201.

202.

203.

204.

205.

206.

207.

208.

209.

210.

211.

212.

213.

214.

215.

216.

217.

218.

219.

220.

221.

222.

223.

224.

225.

226.

227.

228.

229.

230.

231.

232.

233.

234.

235.

236.

237.

238.

239.

240.

241.

242.

243.

244.

245.

246.

247.

248.

249.

250.

251.

252.

253.

254.

255.

256.

Representative compounds of the invention also include, but are notlimited to, the following compounds (example 257 to example 264 in Table2) according to Formula IX wherein R, -L₂-W-L₁-,

R′ and G are delineated for each example in Table 2.

TABLE 2 Example # R —L₂—W—L₁—

R′ G 257.

258.

259.

260.

261.

262.

263.

264.

Representative compounds of the invention also include, but are notlimited to, the following compounds (example 265 to example 272 in Table3) according to Formula X wherein R, -L₂-W-L₁-,

R′ and G are delineated for each example in Table 3.

TABLE 3 Example # R —L₂—W—L₁—

R′ G 265.

266.

267.

268.

269.

270.

271.

272.

In addition, representative compounds of the invention also include, butare not limited to, the following compounds (example 273 to example 299in Table 4) according to Formula XI, wherein R,

R′ and G are delineated for each example in Table 4.

TABLE 4 Exaaws mple# R

R′ G 273.

274.

275.

276.

277.

278.

279.

280.

281.

282.

283.

284.

285.

286.

287.

288.

289.

290.

291.

292.

293.

294.

295.

296.

297.

298.

299.

The present invention also features pharmaceutical compositionscomprising a compound of the invention, or a pharmaceutically acceptablesalt, ester or prodrug thereof. In one embodiment, the present inventionfeatures pharmaceutical compositions comprising a therapeuticallyeffective amount of a compound of the invention, or a pharmaceuticallyacceptable salt, ester or prodrug thereof, in combination with apharmaceutically acceptable carrier or excipient. In another embodiment,the invention features methods of treating a hepatitis C infection in asubject in need of such treatment with said pharmaceutical composition.

In addition, the present invention features methods of using compoundsof the present invention or pharmaceutically acceptable salts thereof totreat HCV infection. The methods comprise administering to an HCVpatient in need thereof an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof.

Preferably, the compound is a compound having Formula VII as describedabove.

It was unexpectedly discovered that the compounds of the invention cansignificantly inhibit or suppress certain HCV genotype 1 and 3 variants(e.g., genotype 1a R₁₅₅K, D168E or D168V variants, genotype 1b R₁₅₅K orD168V variants, or genotype 3a S138T, A166T or Q168R variants). Clinicaltrials and replicon cell assays have identified HCV variants that areresistant to many known protease inhibitors. For instance, the R₁₅₅Kvariants have been shown to confer low-level resistance to telaprevirand boceprevir and confer high-level resistance to BILN 2061 anddanoprevir (ITMN-191). See Bartels et al., THE JOURNAL OF INFECTIOUSDISEASES 198:800-807 (2008). See also Lu et al., ANTIMICROBIAL AGENTSAND CHEMOTHERAPY, 48:2260-2266 (2004); and Zhou et al., THE JOURNAL OFBIOLOGICAL CHEMISTRY, 282:22619-22628 (2007). Viral load rebound, whichoften indicates treatment failure, has been observed in patientsreceiving treatment with danoprevir after the R₁₅₅K variants emerge. Seewww.natap.org/2010/AASLD/AASLD_84.htm (61th Annual Meeting of theAmerican Association for the Study of Liver Diseases, Boston, Mass.,Oct. 30-Nov. 3, 2010). Likewise, viral load rebound has been reported inpatients receiving treatment with vaniprevir (MK-7009). R₁₅₅K or D168Vvariants have been detected in these patients, suggesting resistance orreduced susceptibility of these variants to vaniprevir. Seewww.natap.org/2009/EASL/EASL_27.htm (EASL 44th Annual Meeting, April2009, Copenhagen, Denmark). Moreover, HCV variants harboring R₁₅₅K havebeen detected as the predominant quasispecies in some treatment-naïvepatients. See Salloum et al., ANTIVIRAL RESEARCH 87:272-275 (2010).Accordingly, with significantly improved inhibitory activities againstwild-type as well as variants, the compounds of the present inventionenable an effective and broad-spectrum treatment for HCV infections.

In one aspect, the present invention features methods of treating HCVvariants. The methods comprise administering to patients infected withor harboring such variants an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof. These patientscan be treatment-naïve patients or treatment-experienced patients. Inone embodiment, the patient receiving treatment according to this aspectof the invention harbors a variant selected from genotype 1a R₁₅₅K,D168E or D168V variants, genotype 1b R₁₅₅K or D168V variants, orgenotype 3a A166T or Q168R variants. In another embodiment, the patientharbors an HCV variant selected from genotype 1 R₁₅₅K or D168V variantsor genotype 3 Q168R variants. For example, the patient can harbor avariant selected from genotype 1a R₁₅₅K or D168V variants, genotype 1bR₁₅₅K or D168V variants, or genotype 3s Q168R variants. In yet anotherembodiment, the patient harbors a variant selected from genotype 1 R₁₅₅Kor D168V variants, e.g., genotype 1a R₁₅₅K or D168V variants or genotype1b R₁₅₅K or D168V variants. In one example, the patient harbors agenotype 1 R₁₅₅K variant (e.g., a genotype 1a or 1b R₁₅₅K variant). Inanother example, the patient harbors a genotype 1 D168V variant (e.g., agenotype 1a or 1b D168V variant).

The patients treated according to this aspect of the invention may havepreviously received but failed a treatment regimen containing anotherHCV protease inhibitor. The other HCV protease inhibitor(s) used in theprior treatment can be selected from, for example and withoutlimitation, telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir,TMC-435 (Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335(Boehringer Ingelheim), BMS-650032 (BMS), or a combination thereof.

Preferably, the compound employed in this aspect of the invention is acompound having Formula VII as described above or a pharmaceuticallyacceptable salt thereof. More preferably, the compound employed in thisaspect of the invention is selected from compounds of Examples 1, 2, 4,5, 6, 8, 34, 36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280,281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294,295, 296, or 297, or pharmaceutically acceptable salts thereof. Highlypreferably, the compound employed in this aspect of the invention isselected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294,296 or 297, or pharmaceutically acceptable salts thereof.

In another aspect, the present invention features methods of treatingHCV patients who have previously received a treatment regimen containinganother HCV protease inhibitor. The methods comprise administering tosaid patients an effective amount of a compound of the invention or apharmaceutically acceptable salt thereof. Without limiting the presentinvention to any particular theory, these treatment-experienced patientsmay harbor resistant variants or be prone to HCV mutations and, as aresult, be less responsive to other protease inhibitors (e.g.,telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435(Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (BoehringerIngelheim), BMS-650032 (BMS), or a combination thereof). Preferably, thecompound employed in this aspect of the invention is a compound havingFormula VII as described above or a pharmaceutically acceptable saltthereof. More preferably, the compound employed in this aspect of theinvention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34,36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282,283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296,297, 298 or 299, or pharmaceutically acceptable salts thereof. Highlypreferably, the compound employed in this aspect of the invention can beselected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294,296 or 297, or pharmaceutically acceptable salts thereof.

Moreover, the present invention features methods of treating HCVpatients infected with genotype 3 HCV viruses. These methods are basedon the unexpected finding that the compounds of the invention areeffective in inhibiting HCV genotype 3 viruses including certainvariants (e.g., A166T, Q168R or S138T variants). These methods compriseadministering to said patients an effective amount of a compound of theinvention or a pharmaceutically acceptable salt thereof. Preferably, thecompound employed in this aspect of the invention is a compound havingFormula VII as described above or a pharmaceutically acceptable saltthereof. More preferably, the compound employed in this aspect of theinvention is selected from compounds of Examples 1, 2, 4, 5, 6, 8, 34,36, 40, 65, 89, 90, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282,283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296,297, 298 or 299, or pharmaceutically acceptable salts thereof. Highlypreferably, the compound employed in this aspect of the invention can beselected from compounds of Examples 5, 6, 275, 276, 287, 288, 289, 294,296 or 297, or pharmaceutically acceptable salts thereof.

The present invention also features the use of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for themanufacture of a medication for the treatment of HCV variants. Forinstance, the patients being treated may be infected with or harbor avariant selected from genotype 1a R₁₅₅K, D168E or D168V variants,genotype 1b R₁₅₅K or D168V variants, or genotype 3a A166T or Q168Rvariants. In addition, the present invention features the use of acompound of the invention, or a pharmaceutically acceptable saltthereof, for the manufacture of a medication for the treatment oftreatment-experienced HCV patients who have previously received butfailed a treatment containing another HCV protease inhibitor (e.g.,telaprevir, boceprevir, danoprevir, vaniprevir, narlaprevir, TMC-435(Tibotec), BILN 2061 (Boehringer Ingelheim), BI-201335 (BoehringerIngelheim), BMS-650032 (BMS), or a combination thereof). Furthermore,the present invention contemplates the use of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for themanufacture of a medication for the treatment of HCV patients infectedwith genotype 3 HCV (including genotype 3 variants, such as genotype 3sA166T, Q168R or S138T variants).

In the methods described herein, a compound of the present invention ora pharmaceutically acceptable salt thereof can be administered alone, orin combination with one or more other anti-HCV agents, such as HCVpolymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors,CD81 inhibitors, cyclophilin inhibitors, internal ribosome entry site(IRES) inhibitors or any combinations thereof. Interferon, ribavirin orboth can also be included in the treatment. For example, the methodsdescribed herein can further comprise administering to the patientpeginterferon-alpha and ribavirin. Different agents can be administeredsimultaneously or sequentially. The dosing frequency of each agent in atreatment regimen can be the same or different. For instance, a compoundof the invention can be dosed once daily and ribavirin can be dosedtwice daily.

Compounds of the present invention can be administered as the soleactive pharmaceutical agent, or used in combination with one or moreagents to treat or prevent hepatitis C infections or the symptomsassociated with HCV infection. Other agents to be administered incombination with a compound or combination of compounds of the inventioninclude therapies for disease caused by HCV infection that suppressesHCV viral replication by direct or indirect mechanisms. These includeagents such as host immune modulators (for example, interferon-alpha,pegylated interferon-alpha, interferon-beta, interferon-gamma, CpGoligonucleotides and the like), cyclophilins (e.g., Debio 025), orantiviral compounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase (for example, ribavirin and the like). Alsoincluded are cytokines that modulate immune function. Also included arevaccines comprising HCV antigens or antigen adjuvant combinationsdirected against HCV. Also included are agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like. Other agents to be administered incombination with a compound of the present invention include any agentor combination of agents that inhibit the replication of HCV bytargeting proteins of the viral genome involved in the viralreplication. These agents include but are not limited to otherinhibitors of HCV RNA dependent RNA polymerase such as, for example,nucleoside type polymerase inhibitors described in WO0190121(A2), orU.S. Pat. No. 6,348,587B1 or WO0160315 or WO00132153 or non-nucleosideinhibitors such as, for example, benzimidazole polymerase inhibitorsdescribed in EP 1162196A1 or WO00204425 or inhibitors of HCV proteasesuch as, for example, peptidomimetic type inhibitors such as BILN2061and the like or inhibitors of HCV helicase.

Other agents to be administered in combination with a compound of thepresent invention include any agent or combination of agents thatinhibit the replication of other viruses for co-infected individuals.These agents include but are not limited to therapies for disease causedby hepatitis B (HBV) infection or therapies for disease caused by humanimmunodeficiency virus (HIV) infection.

Accordingly, one aspect of the invention is directed to a method fortreating or preventing an infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents selected from the group consisting of a host immunemodulator and a second antiviral agent, or a combination thereof, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Examples of the host immune modulator are, but not limited to,interferon-alpha, pegylated-interferon-alpha, interferon-beta,interferon-gamrna, a cytokine, a vaccine, and a vaccine comprising anantigen and an adjuvant, and said second antiviral agent inhibitsreplication of HCV either by inhibiting host cellular functionsassociated with viral replication or by targeting proteins of the viralgenome.

A further aspect of the invention is directed to a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment an agent orcombination of agents that treat or alleviate symptoms of HCV infectionincluding cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the invention, or a pharmaceutically acceptable salt,stereoisomer, tautomer, prodrug, salt of a prodrug, or combinationthereof. Yet another aspect of the invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the invention, or a pharmaceuticallyacceptable salt, stereoisomer, tautomer, prodrug, salt of a prodrug, orcombination thereof. An agent that treats patients for disease caused byhepatitis B (HBV) infection may be for example, but not limited thereto,L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combinationthereof. Example of the RNA-containing virus includes, but not limitedto, hepatitis C virus (HCV).

Another aspect of the invention provides a method of treating orpreventing infection caused by an RNA-containing virus comprisingco-administering to a patient in need of such treatment one or moreagents that treat patients for disease caused by human immunodeficiencyvirus (HIV) infection, with a therapeutically effective amount of acompound or a combination of compounds of the invention, or apharmaceutically acceptable salt, stereoisomer, tautomer, prodrug, saltof a prodrug, or combination thereof. An example of the RNA-containingvirus includes, but not limited to, hepatitis C virus (HCV). Inaddition, the present invention provides the use of a compound or acombination of compounds of the invention, or a therapeuticallyacceptable salt form, stereoisomer, or tautomer, prodrug, salt of aprodrug, or combination thereof, and one or more agents selected fromthe group consisting of a host immune modulator and a second antiviralagent, or a combination thereof, to prepare a medicament for thetreatment of an infection caused by an RNA-containing virus in apatient, particularly hepatitis C virus. Examples of the host immunemodulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compound orcompounds of the invention, together with one or more agents as definedherein above, can be employed in pure form or, where such forms exist,in pharmaceutically acceptable salt form, prodrug, salt of a prodrug, orcombination thereof. Alternatively, such combination of therapeuticagents can be administered as a pharmaceutical composition containing atherapeutically effective amount of the compound or combination ofcompounds of interest, or their pharmaceutically acceptable salt form,prodrugs, or salts of the prodrug, in combination with one or moreagents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, further aspect of the invention is directed to a method oftreating or preventing infection caused by an RNA-containing virus,particularly a hepatitis C virus (HCV), comprising administering to apatient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt, stereoisomer, or tautomer, prodrug,salt of a prodrug, or combination thereof, one or more agents as definedhereinabove, and a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to, agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other anti-HCV agents include those agents that are effective fordiminishing or preventing the progression of hepatitis C relatedsymptoms or disease. Such agents include but are not limited toimmunomodulatory agents, inhibitors of HCV NS3 protease, otherinhibitors of HCV polymerase, inhibitors of another target in the HCVlife cycle and other anti-HCV agents, including but not limited to,ribavirin, amantadine, levovirin and viramidine.

Immunomodulatory agents include those agents (compounds or biologicals)that are effective to enhance or potentiate the immune system responsein a mammal. Immunomodulatory agents include, but are not limited to,inosine monophosphate dehydrogenase inhibitors such as VX-497(merimepodib, Vertex Pharmaceuticals), class I interferons, class IIinterferons, consensus interferons, asialo-interferons pegylatedinterferons and conjugated interferons, including but not limited to,interferons conjugated with other proteins including but not limited to,human albumin. Class I interferons are a group of interferons that allbind to receptor type I, including both naturally and syntheticallyproduced class I interferons, while class II interferons all bind toreceptor type II. Examples of class I interferons include, but are notlimited to, [alpha]-, [beta]-, [delta]-, [omega]-, and[tau]-interferons, while examples of class II interferons include, butare not limited to, [gamma]-interferons.

Inhibitors of HCV NS3 protease include agents (compounds or biologicals)that are effective to inhibit the function of HCV NS3 protease in amammal. Inhibitors of HCV NS3 protease include, but are not limited to,those compounds described in WO 99/07733, WO 99/07734, WO 00/09558, WO00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO2004/101605, WO 2004/103996, WO 2005/028501, WO 2005/070955, WO2006/000085, WO 2006/007700 and WO 2006/007708 (all by BoehringerIngelheim), WO 02/060926, WO 03/053349, WO03/099274, WO 03/099316, WO2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO2005/051410, WO 2005/054430 (all by BMS), WO 2004/072243, WO2004/093798, WO 2004/113365, WO 2005/010029 (all by Enanta), WO2005/037214 (Intermune) and WO 2005/051980 (Schering), and thecandidates identified as VX-950, ITMN-191 and SCH 503034.

Inhibitors of HCV polymerase include agents (compounds or biologicals)that are effective to inhibit the function of an HCV polymerase. Suchinhibitors include, but are not limited to, non-nucleoside andnucleoside inhibitors of HCV NS5B polymerase. Examples of inhibitors ofHCV polymerase include but are not limited to those compounds describedin: WO 02/04425, WO 03/007945, WO 03/010140, WO 03/010141, WO2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (all byBoehringer Ingelheim), WO 2005/049622 (Japan Tobacco), WO 2005/014543(Japan Tobacco), WO 2005/012288 (Genelabs), WO 2004/087714 (IRBM), WO03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (JapanTobacco), and WO 01/47883 (Japan Tobacco), and the clinical candidatesXTL-2125, HCV 796, R-1626 and NM 283.

Inhibitors of another target in the HCV life cycle include agents(compounds or biologicals) that are effective to inhibit the formationand/or replication of HCV other than by inhibiting the function of theHCV NS3 protease. Such agents may interfere with either host or HCVviral mechanisms necessary for the formation and/or replication of HCV.Inhibitors of another target in the HCV life cycle include, but are notlimited to, entry inhibitors, agents that inhibit a target selected froma helicase, a NS2/3 protease and an internal ribosome entry site (IRES)and agents that interfere with the function of other viral targetsincluding but not limited to, an NS5A protein and an NS4B protein.

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to, humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus, also contemplated is combination therapy to treatsuch co-infections by co-administering a compound according to thepresent invention with at least one of an HIV inhibitor, an HAVinhibitor and an HBV inhibitor.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise inhibitor(s) of other targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, and internal ribosome entry site (IRES).

According to another embodiment, the pharmaceutical compositions of thepresent invention may further comprise another anti-viral,anti-bacterial, anti-fungal or anti-cancer agent, or an immunemodulator, or another therapeutic agent.

According to still another embodiment, the present invention includesmethods of treating viral infection such as, but not limited to,hepatitis C infections in a subject in need of such treatment byadministering to said subject an effective amount of a compound of thepresent invention or a pharmaceutically acceptable salt, ester, orprodrug thereof.

According to a further embodiment, the present invention includesmethods of treating hepatitis C infections in a subject in need of suchtreatment by administering to said subject an anti-HCV virally effectiveamount or an inhibitory amount of a pharmaceutical composition of thepresent invention.

An additional embodiment of the present invention includes methods oftreating biological samples by contacting the biological samples withthe compounds of the present invention.

Yet a further aspect of the present invention is a process of making anyof the compounds delineated herein employing any of the synthetic meansdelineated herein.

Definitions

Listed below are definitions of various terms used to describe thisinvention. These definitions apply to the terms as they are usedthroughout this specification and claims, unless otherwise limited inspecific instances, either individually or as part of a larger group.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication.

Viral infection may be determined by measuring virus antibody titer insamples of a biological fluid, such as blood, using, e.g., enzymeimmunoassay. Other suitable diagnostic methods include molecular basedtechniques, such as RT-PCR, direct hybrid capture assay, nucleic acidsequence based amplification, and the like. A virus may infect an organ,e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronicliver disease and hepatocellular carcinoma.

The term “anti-cancer agent” refers to a compound or drug capable ofpreventing or inhibiting the advancement of cancer. Examples of suchagents include cis-platin, actinomycin D, doxorubicin, vincristine,vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol,colchicine, cyclosporin A, phenothiazines or thioxantheres.

The term “anti-fungal agent” shall used to describe a compound which maybe used to treat a fungus infection other than 3-AP, 3-AMP or prodrugsof 3-AP and 3-AMP according to the present invention. Anti-fungal agentsaccording to the present invention include, for example, terbinafine,fluconazole, itraconazole, posaconazole, clotrimazole, griseofulvin,nystatin, tolnaftate, caspofungin, amphotericin B, liposomalamphotericin B, and amphotericin B lipid complex.

The term “antibacterial agent” refers to both naturally occurringantibiotics produced by microorganisms to suppress the growth of othermicroorganisms, and agents synthesized or modified in the laboratorywhich have either bactericidal or bacteriostatic activity, e.g.,β-lactam antibacterial agents, glycopeptides, macrolides, quinolones,tetracyclines, and aminoglycosides. In general, if an antibacterialagent is bacteriostatic, it means that the agent essentially stopsbacterial cell growth (but does not kill the bacteria); if the agent isbacteriocidal, it means that the agent kills the bacterial cells (andmay stop growth before killing the bacteria).

The term “immune modulator” refers to any substance meant to alter theworking of the humoral or cellular immune system of a subject. Suchimmune modulators include inhibitors of mast cell-mediated inflammation,interferons, interleukins, prostaglandins, steroids, cortico-steroids,colony-stimulating factors, chemotactic factors, etc.

The term “C₁-C₆ alkyl,” or “C₁-C₈ alkyl,” as used herein, refer tosaturated, straight- or branched-chain hydrocarbon radicals containingbetween one and six, or one and eight carbon atoms, respectively.Examples of C₁-C₆ alkyl radicals include, but are not limited to,methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl,n-hexyl radicals; and examples of C₁-C₈ alkyl radicals include, but arenot limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl,neopentyl, n-hexyl, heptyl, octyl radicals.

The term “C₂-C₆ alkenyl,” or “C₂-C₈ alkenyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety by the removal of asingle hydrogen atom wherein the hydrocarbon moiety has at least onecarbon-carbon double bond and contains from two to six, or two to eightcarbon atoms, respectively. Alkenyl groups include, but are not limitedto, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl,heptenyl, octenyl and the like.

The term “C₂-C₆ alkynyl,” or “C₂-C₈ alkynyl,” as used herein, denote amonovalent group derived from a hydrocarbon moiety by the removal of asingle hydrogen atom wherein the hydrocarbon moiety has at least onecarbon-carbon triple bond and contains from two to six, or two to eightcarbon atoms, respectively. Representative alkynyl groups include, butare not limited to, for example, ethynyl, 1-propynyl, 1-butynyl,heptynyl, octynyl and the like.

The term “carbocycle” refers to a saturated (e.g., “cycloalkyl”),partially saturated (e.g., “cycloalkenyl” or “cycloalkynyl”) orcompletely unsaturated (e.g., “aryl”) ring system containing zeroheteroatom ring atom. “Ring atoms” or “ring members” are the atoms boundtogether to form the ring or rings. Where a carbocycle group is adivalent moiety linking two other elements in a depicted chemicalstructure (such as Z in Formula IA), the carbocycle group can beattached to the two other elements through any two substitutable ringatoms. A C₄-C₆ carbocycle has 4-6 ring atoms.

The term “C₃-C₈-cycloalkyl”, or “C₃-C₁₂-cycloalkyl,” as used herein,denotes a monovalent group derived from a monocyclic or polycyclicsaturated carbocyclic ring compound by the removal of a single hydrogenatom where the saturated carbocyclic ring compound has from 3 to 8, orfrom 3 to 12, ring atoms, respectively. Examples of C₃-C₈-cycloalkylinclude, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl and cyclooctyl; and examples ofC₃-C₁₂-cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2.2]octyl.

The term “C₃-C₈-cycloalkenyl”, or “C₃-C₁₂-cycloalkenyl” as used herein,denote a monovalent group derived from a monocyclic or polycycliccarbocyclic ring compound having at least one carbon-carbon double bondby the removal of a single hydrogen atom where the carbocyclic ringcompound has from 3 to 8, or from 3 to 12, ring atoms, respectively.Examples of C₃-C₈-cycloalkenyl include, but not limited to,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cyclooctenyl, and the like; and examples of C₃-C₁₂-cycloalkenyl include,but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like.

The term “aryl,” as used herein, refers to a mono- or bicycliccarbocyclic ring system having one or two aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyland the like.

The term “arylalkyl,” as used herein, refers to a C₁-C₃ alkyl or C₁-C₆alkyl residue attached to an aryl ring. Examples include, but are notlimited to, benzyl, phenethyl and the like.

The term “heteroaryl,” as used herein, refers to a mono-, bi-, ortri-cyclic aromatic radical or ring having from five to ten ring atomsof which at least one ring atom is selected from S, O and N; wherein anyN or S contained within the ring may be optionally oxidized. Heteroarylincludes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl,pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl,thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzooxazolyl, quinoxalinyl, and thelike.

The term “heteroarylalkyl,” as used herein, refers to a C₁-C₃ alkyl orC₁-C₆ alkyl residue residue attached to a heteroaryl ring. Examplesinclude, but are not limited to, pyridinylmethyl, pyrimidinylethyl andthe like.

The term “substituted” as used herein, refers to independent replacementof one, two, or three or more of the hydrogen atoms thereon withsubstituents including, but not limited to, —F, —Cl, —Br, —I, —OH,protected hydroxy, —NO₂, —CN, —NH₂, N₃, protected amino, alkoxy,thioalkoxy, oxo, -halo-C₁-C₁₂-alkyl, -halo-C₂-C₁₂-alkenyl,-halo-C₂-C₁₂-alkynyl, -halo-C₃-C₁₂-cycloalkyl, —NH—C₁-C₁₂-alkyl,—NH—C₂-C₁₂-alkenyl, —NH—C₂-C₁₂-alkynyl, —NH—C₃-C₁₂-cycloalkyl, —NH-aryl,—NH-heteroaryl, —NH-heterocycloalkyl, -dialkylamino, -diarylamino,-diheteroarylamino, —O—C₁-C₁₂-alkyl, —O—C₂-C₁₂-alkenyl,—O—C₂-C₁₂-alkynyl, —O—C₃-C₁₂-cycloalkyl, —O-aryl, —O— heteroaryl,—O-heterocycloalkyl, —C(O)— C₁-C₁₂-alkyl, —C(O)— C₂-C₁₂-alkenyl, —C(O)—C₂-C₁₂-alkynyl, —C(O)—C₃-C₁₂-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl,—C(O)-heterocycloalkyl, —CONH₂, —CONH— C₁-C₁₂-alkyl, —CONH—C₂-C₁₂-alkenyl, —CONH— C₂-C₁₂-alkynyl, —CONH—C₃-C₁₂-cycloalkyl,—CONH-aryl, —CONH-heteroaryl, —CONH-heterocycloalkyl, —OCO₂—C₁-C₁₂-alkyl, —OCO₂— C₂-C₁₂-alkenyl, —OCO₂— C₂-C₁₂-alkynyl,—OCO₂—C₃-C₁₂-cycloalkyl, —OCO₂-aryl, —OCO₂-heteroaryl,—OCO₂-heterocycloalkyl, —OCONH₂, —OCONH— C₁-C₁₂-alkyl, —OCONH—C₂-C₁₂-alkenyl, —OCONH— C₂-C₁₂-alkynyl, —OCONH— C₃-C₁₂-cycloalkyl,—OCONH— aryl, —OCONH— heteroaryl, —OCONH— heterocycloalkyl, —NHC(O)—C₁-C₁₂-alkyl, —NHC(O)—C₂-C₁₂-alkenyl, —NHC(O)—C₂-C₁₂-alkynyl,—NHC(O)—C₃-C₁₂-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl,—NHC(O)-heterocycloalkyl, —NHCO₂— C₁-C₁₂-alkyl, —NHCO₂— C₂-C₁₂-alkenyl,—NHCO₂— C₂-C₁₂-alkynyl, —NHCO₂— C₃-C₁₂-cycloalkyl, —NHCO₂— aryl, —NHCO₂—heteroaryl, —NHCO₂— heterocycloalkyl, —NHC(O)NH₂, —NHC(O)NH—C₁-C₁₂-alkyl, —NHC(O)NH—C₂-C₁₂-alkenyl, —NHC(O)NH—C₂-C₁₂-alkynyl,—NHC(O)NH—C₃-C₁₂-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH— heteroaryl,—NHC(O)NH-heterocycloalkyl, NHC(S)NH₂, —NHC(S)NH— C₁-C₁₂-alkyl,—NHC(S)NH—C₂-C₁₂-alkenyl, —NHC(S)NH—C₂-C₁₂-alkynyl,—NHC(S)NH—C₃-C₁₂-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl,—NHC(S)NH-heterocycloalkyl, —NHC(NH)NH₂, —NHC(NH)NH—C₁-C₁₂-alkyl,—NHC(NH)NH—C₂-C₁₂-alkenyl, —NHC(NH)NH—C₂-C₁₂-alkynyl,—NHC(NH)NH—C₃-C₁₂-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl,—NHC(NH)NH-heterocycloalkyl, —NHC(NH)—C₁-C₁₂-alkyl,—NHC(NH)—C₂-C₁₂-alkenyl, —NHC(NH)—C₂-C₁₂-alkynyl,—NHC(NH)—C₃-C₁₂-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)— heteroaryl,—NHC(NH)-heterocycloalkyl, —C(NH)NH—C₁-C₁₂-alkyl,—C(NH)NH—C₂-C₁₂-alkenyl, —C(NH)NH—C₂-C₁₂-alkynyl,—C(NH)NH—C₃-C₁₂-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH— heteroaryl,—C(NH)NH-heterocycloalkyl, —S(O)—C₁-C₁₂-alkyl, —S(O)—C₂-C₁₂-alkenyl,—S(O)—C₂-C₁₂-alkynyl, —S(O)—C₃-C₁₂-cycloalkyl, —S(O)-aryl,—S(O)-heteroaryl, —S(O)-heterocycloalkyl-SO₂NH₂, —SO₂NH—C₁-C₁₂-alkyl,—SO₂NH—C₂-C₁₂-alkenyl, —SO₂NH—C₂-C₁₂-alkynyl, —SO₂NH—C₃-C₁₂-cycloalkyl,—SO₂NH-aryl, —SO₂NH-heteroaryl, —SO₂NH-heterocycloalkyl,—NHSO₂—C₁—C₁₂-alkyl, —NHSO₂—C₂-C₁₂-alkenyl, —NHSO₂—C₂-C₁₂-alkynyl,—NHSO₂—C₃-C₁₂-cycloalkyl, —NHSO₂-aryl, —NHSO₂-heteroaryl,—NHSO₂-heterocycloalkyl, —CH₂NH₂, —CH₂SO₂CH₃, -aryl, -arylalkyl,-heteroaryl, -heteroarylalkyl, -heterocycloalkyl, —C₃-C₁₂-cycloalkyl,polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, —SH,—S—C₁-C₁₂-alkyl, —S—C₂-C₁₂-alkenyl, —S—C₂-C₁₂-alkynyl,—S—C₃-C₁₂-cycloalkyl, —S-aryl, —S-heteroaryl, —S-heterocycloalkyl,methylthiomethyl, or -L′-R′, wherein L′ is C₁-C₆alkylene,C₂-C₆alkenylene or C₂-C₆alkynylene, and R′ is aryl, heteroaryl,heterocyclic, C₃-C₁₂cycloalkyl or C₃-C₁₂cycloalkenyl. It is understoodthat the aryls, heteroaryls, alkyls, and the like can be furthersubstituted. In some cases, each substituent in a substituted moiety isadditionally optionally substituted with one or more groups, each groupbeing independently selected from —F, —Cl, —Br, —I, —OH, —NO₂, —CN, or—NH₂.

In accordance with the invention, any of the aryls, substituted aryls,heteroaryls and substituted heteroaryls described herein, can be anyaromatic group. Aromatic groups can be substituted or unsubstituted.

It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl andcycloalkenyl moiety described herein can also be an aliphatic group, analicyclic group or a heterocyclic group. An “aliphatic group” isnon-aromatic moiety that may contain any combination of carbon atoms,hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, andoptionally contain one or more units of unsaturation, e.g., doubleand/or triple bonds. An aliphatic group may be straight chained,branched or cyclic and preferably contains between about 1 and about 24carbon atoms, more typically between about 1 and about 12 carbon atoms.In addition to aliphatic hydrocarbon groups, aliphatic groups include,for example, polyalkoxyalkyls, such as polyalkylene glycols, polyamines,and polyimines, for example. Such aliphatic groups may be furthersubstituted. It is understood that aliphatic groups may be used in placeof the alkyl, alkenyl, alkynyl, alkylene, alkenylene, and alkynylenegroups described herein.

The term “alicyclic,” as used herein, denotes a monovalent group derivedfrom a monocyclic or polycyclic saturated carbocyclic ring compound bythe removal of a single hydrogen atom. Examples include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1] heptyl, and bicyclo [2.2.2] octyl. Such alicyclic groups may befurther substituted.

The term “heterocycloalkyl” and “heterocyclic” can be usedinterchangeably and refer to a non-aromatic 3-, 4-, 5-, 6- or 7-memberedring or a bi- or tri-cyclic group fused system, where: (i) each ringcontains between one and three heteroatoms independently selected fromoxygen, sulfur and nitrogen, (ii) each 5-membered ring has 0 to 1 doublebonds and each 6-membered ring has 0 to 2 double bonds, (iii) thenitrogen and sulfur heteroatoms may optionally be oxidized, (iv) thenitrogen heteroatom may optionally be quaternized, (v) any of the aboverings may be fused to a benzene ring, and (vi) the remaining ring atomsare carbon atoms which may be optionally oxo-substituted. Representativeheterocycloalkyl groups include, but are not limited to, [1,3]dioxolane,pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, andtetrahydrofuryl. Such heterocyclic groups may be further substituted togive substituted heterocyclic.

It will be apparent that in various embodiments of the invention, thesubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, arylalkyl, heteroarylalkyl, andheterocycloalkyl are intended to be monovalent or divalent. Thus,alkylene, alkenylene, and alkynylene, cycloaklylene, cycloalkenylene,cycloalkynylene, arylalkylene, hetoerarylalkylene andheterocycloalkylene groups are to be included in the above definitions,and are applicable to provide the formulas herein with proper valency.

The term “hydroxy activating group”, as used herein, refers to a labilechemical moiety which is known in the art to activate a hydroxy group sothat it will depart during synthetic procedures such as in asubstitution or elimination reactions. Examples of hydroxy activatinggroup include, but not limited to, mesylate, tosylate, triflate,p-nitrobenzoate, phosphonate and the like.

The term “activated hydroxy”, as used herein, refers to a hydroxy groupactivated with a hydroxy activating group, as defined above, includingmesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, forexample.

The term “protected hydroxy,” as used herein, refers to a hydroxy groupprotected with a hydroxy protecting group, as defined above, includingbenzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups.

The terms “halo” and “halogen,” as used herein, refer to an atomselected from fluorine, chlorine, bromine and iodine.

The compounds described herein contain one or more asymmetric centersand thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible isomers, aswell as their racemic and optically pure forms. Optical isomers may beprepared from their respective optically active precursors by theprocedures described above, or by resolving the racemic mixtures. Theresolution can be carried out in the presence of a resolving agent, bychromatography or by repeated crystallization or by some combination ofthese techniques, which are known to those skilled in the art. Furtherdetails regarding resolutions can be found in Jacques, et al.,Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981). Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended that the compounds include both E and Z geometric isomers.Likewise, all tautomeric forms are also intended to be included. Theconfiguration of any carbon-carbon double bond appearing herein isselected for convenience only and is not intended to designate aparticular configuration unless the text so states; thus a carbon-carbondouble bond depicted arbitrarily herein as trans may be cis, trans, or amixture of the two in any proportion.

The term “subject” as used herein refers to a mammal. A subjecttherefore refers to, for example, dogs, cats, horses, cows, pigs, guineapigs, and the like. Preferably the subject is a human. When the subjectis a human, the subject may be referred to herein as a patient. As usedherein, the term “pharmaceutically acceptable salt” refers to thosesalts of the compounds formed by the process of the present inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art.

The term “hydroxy protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect a hydroxy groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the hydroxy protecting group as described hereinmay be selectively removed. Hydroxy protecting groups as known in theare described generally in T. H. Greene and P. G., S. M. Wuts,Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons,New York (1999). Examples of hydroxy protecting groups includebenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, methoxycarbonyl, tert-butoxycarbonyl,isopropoxycarbonyl, diphenylmethoxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-furfuryloxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl,trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl,2,2,2-trichloroethyl, 2-trimethylsilyl ethyl, 1,1-dimethyl-2-propenyl,3-methyl-3-butenyl, allyl, benzyl, para-methoxybenzyldiphenylmethyl,triphenylmethyl (trityl), tetrahydrofuryl, methoxymethyl,methylthiomethyl, benzyloxymethyl, 2,2,2-triehloroethoxymethyl,2-(trimethyl silyl)ethoxymethyl, methanesulfonyl, para-toluenesulfonyl,trimethylsilyl, triethylsilyl, triisopropylsilyl, and the like.Preferred hydroxy protecting groups for the present invention are acetyl(Ac or —C(O)CH₃), benzoyl (Bz or —C(O)C₆H5), and trimethylsilyl (TMS or—Si(CH₃)₃). Berge, et al. describes pharmaceutically acceptable salts indetail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can beprepared in situ during the final isolation and purification of thecompounds of the invention, or separately by reacting the free basefunction with a suitable organic acid. Examples of pharmaceuticallyacceptable salts include, but are not limited to, nontoxic acid additionsalts e.g., salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include, but are not limited to,adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and arylsulfonate.

The term “amino protecting group,” as used herein, refers to a labilechemical moiety which is known in the art to protect an amino groupagainst undesired reactions during synthetic procedures. After saidsynthetic procedure(s) the amino protecting group as described hereinmay be selectively removed. Amino protecting groups as known in the aredescribed generally in T. H. Greene and P. G. M. Wuts, Protective Groupsin Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of amino protecting groups include, but are not limited to,t-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyloxycarbonyl, and thelike.

As used herein, the term “pharmaceutically acceptable ester” refers toesters of the compounds formed by the process of the present inventionwhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Suitableester groups include, for example, those derived from pharmaceuticallyacceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic,cycloalkanoic and alkanedioic acids, in which each alkyl or alkenylmoiety advantageously has not more than 6 carbon atoms. Examples ofparticular esters include, but are not limited to, formates, acetates,propionates, butyrates, acrylates and ethylsuccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers tothose prodrugs of the compounds formed by the process of the presentinvention which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswith undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use, as well as the zwitterionic forms, where possible,of the compounds of the present invention. “Prodrug”, as used hereinmeans a compound, which is convertible in vivo by metabolic means (e.g.by hydrolysis) to afford any compound delineated by the formulae of theinstant invention. Various forms of prodrugs are known in the art, forexample, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier(1985); Widder, et al. (ed.), Methods in Enzymology, Vol. 4, AcademicPress (1985); Krogsgaard-Larsen, et al., (ed). “Design and Applicationof Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191(1991); Bundgaard, et al., Journal of Drug Deliver Reviews,8:1-38(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq.(1988); Higuchi and Stella (eds.) Prodrugs as Novel Drug DeliverySystems, American Chemical Society (1975); and Bernard Testa & JoachimMayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry,Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

The term “aprotic solvent,” as used herein, refers to a solvent that isrelatively inert to proton activity, i.e., not acting as a proton-donor.Examples include, but are not limited to, hydrocarbons, such as hexaneand toluene, for example, halogenated hydrocarbons, such as, forexample, methylene chloride, ethylene chloride, chloroform, and thelike, heterocyclic compounds, such as, for example, tetrahydrofuran andN-methylpyrrolidinone, and ethers such as diethyl ether,bis-methoxymethyl ether. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofaprotic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

The terms “protogenic organic solvent” or “protic solvent” as usedherein, refer to a solvent that tends to provide protons, such as analcohol, for example, methanol, ethanol, propanol, isopropanol, butanol,t-butanol, and the like. Such solvents are well known to those skilledin the art, and individual solvents or mixtures thereof may be preferredfor specific compounds and reaction conditions, depending upon suchfactors as the solubility of reagents, reactivity of reagents andpreferred temperature ranges, for example. Further discussions ofprotogenic solvents may be found in organic chemistry textbooks or inspecialized monographs, for example: Organic Solvents PhysicalProperties and Methods of Purification, 4th ed., edited by John A.Riddick et al., Vol. II, in the Techniques of Chemistry Series, JohnWiley & Sons, N Y, 1986.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds. Theterm “stable”, as used herein, refers to compounds which possessstability sufficient to allow manufacture and which maintains theintegrity of the compound for a sufficient period of time to be usefulfor the purposes detailed herein (e.g., therapeutic or prophylacticadministration to a subject).

The synthesized compounds can be separated from a reaction mixture andfurther purified by a method such as column chromatography, highpressure liquid chromatography, or recrystallization. Additionally, thevarious synthetic steps may be performed in an alternate sequence ororder to give the desired compounds. In addition, the solvents,temperatures, reaction durations, etc. delineated herein are forpurposes of illustration only and variation of the reaction conditionscan produce the desired bridged macrocyclic products of the presentinvention. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein include, for example, those described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995).

The compounds of this invention may be modified by appending variousfunctionalities via synthetic means delineated herein to enhanceselective biological properties. Such modifications include those whichincrease biological penetration into a given biological system (e.g.,blood, lymphatic system, central nervous system), increase oralavailability, increase solubility to allow administration by injection,alter metabolism and alter rate of excretion.

Pharmaceutical Compositions

The pharmaceutical compositions of the present invention comprise atherapeutically effective amount of a compound of the present inventionformulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator. The pharmaceuticalcompositions of this invention can be administered to humans and otheranimals orally, rectally, parenterally, intracisternally,intravaginally, intraperitoneally, topically (as by powders, ointments,or drops), buccally, or as an oral or nasal spray.

The pharmaceutical compositions of this invention may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions of this invention may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose, any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or: a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants suchas chlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

Antiviral Activity

An inhibitory amount or dose of the compounds of the present inventionmay range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively fromabout 1 to about 50 mg/Kg. Inhibitory amounts or doses will also varydepending on route of administration, as well as the possibility ofco-usage with other agents.

According to the methods of treatment of the present invention, viralinfections are treated or prevented in a subject such as a human orlower mammal by administering to the subject an anti-hepatitis C virallyeffective amount or an inhibitory amount of a compound of the presentinvention, in such amounts and for such time as is necessary to achievethe desired result. An additional method of the present invention is thetreatment of biological samples with an inhibitory amount of a compoundof composition of the present invention in such amounts and for suchtime as is necessary to achieve the desired result.

The term “anti-hepatitis C virally effective amount” of a compound ofthe invention, as used herein, mean a sufficient amount of the compoundso as to decrease the viral load in a biological sample or in a subject(e.g., resulting in at least 10%, preferably at least 50%, morepreferably at least 80%, and most preferably at least 90% or 95%,reduction in viral load). As well understood in the medical arts, ananti-hepatitis C virally effective amount of a compound of thisinvention will be at a reasonable benefit/risk ratio applicable to anymedical treatment.

The term “inhibitory amount” of a compound of the present inventionmeans a sufficient amount to decrease the hepatitis C viral load in abiological sample or a subject (e.g., resulting in at least 10%,preferably at least 50%, more preferably at least 80%, and mostpreferably at least 90% or 95%, reduction in viral load). It isunderstood that when said inhibitory amount of a compound of the presentinvention is administered to a subject it will be at a reasonablebenefit/risk ratio applicable to any medical treatment as determined bya physician. The term “biological sample(s),” as used herein, means asubstance of biological origin intended for administration to a subject.Examples of biological samples include, but are not limited to, bloodand components thereof such as plasma, platelets, subpopulations ofblood cells and the like; organs such as kidney, liver, heart, lung, andthe like; sperm and ova; bone marrow and components thereof; or stemcells. Thus, another embodiment of the present invention is a method oftreating a biological sample by contacting said biological sample withan inhibitory amount of a compound or pharmaceutical composition of thepresent invention.

Upon improvement of a subject's condition, a maintenance dose of acompound, composition or combination of this invention may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level, treatment should cease. Thesubject may, however, require intermittent treatment on a long-termbasis upon any recurrence of disease symptoms.

It will be understood, however, that the total daily usage of thecompounds and compositions of the present invention will be decided bythe attending physician within the scope of sound medical judgment. Thespecific inhibitory dose for any particular patient will depend upon avariety of factors including the disorder being treated and the severityof the disorder; the activity of the specific compound employed; thespecific composition employed; the age, body weight, general health, sexand diet of the patient; the time of administration, route ofadministration, and rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed; and like factors well known in themedical arts.

The total daily inhibitory dose of the compounds of this inventionadministered to a subject in single or in divided doses can be inamounts, for example, from 0.01 to 50 mg/kg body weight or more usuallyfrom 0.1 to 25 mg/kg body weight. Single dose compositions may containsuch amounts or submultiples thereof to make up the daily dose. Ingeneral, treatment regimens according to the present invention compriseadministration to a patient in need of such treatment from about 10 mgto about 1000 mg of the compound(s) of this invention per day in singleor multiple doses.

Unless otherwise defined, all technical and scientific terms used hereinare accorded the meaning commonly known to one with ordinary skill inthe art. All publications, patents, published patent applications, andother references mentioned herein are hereby incorporated by referencein their entirety.

Abbreviations

Abbreviations which have been used in the descriptions of the schemesand the examples that follow are:

-   -   ACN for acetonitrile;    -   BME for 2-mercaptoethanol;    -   BOP for benzotriazol-1-yloxy-tris(dimethylamino)phosphonium        hexafluorophosphate;    -   CDI for carbonyldiimidazole;    -   COD for cyclooctadiene;    -   DAST for diethylaminosulfur trifluoride;    -   DABCYL for        6-(N-4′-carboxy-4-(dimethylamino)azobenzene)-aminohexyl-1-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramidite;    -   DBU for 1,8-Diazabicycloundec-7-ene;    -   DCC for N, N′-dicyclohexylcarbodiimide;    -   DCM for dichloromethane;    -   DIAD for diisopropyl azodicarboxylate;    -   DIBAL-H for diisobutylaluminum hydride;    -   DIPEA for diisopropyl ethylamine;    -   DMAP for N,N-dimethylaminopyridine;    -   DME for ethylene glycol dimethyl ether;    -   DMEM for Dulbecco's Modified Eagles Media;    -   DMF for N,N-dimethyl formamide;    -   DMSO for dimethylsulfoxide;    -   DSC for N, N′-disuccinimidyl carbonate;    -   DUPHOS for

-   -   EDANS for 5-(2-Amino-ethylamino)-naphthalene-1-sulfonic acid;    -   EDCI or EDC for 1-(3-diethylaminopropyl)-3-ethylcarbodiimide        hydrochloride;    -   EtOAc for ethyl acetate;    -   EtOH for ethyl alcohol;    -   HATU for O        (7-Azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium        hexafluorophosphate;    -   HCl for hydrochloric acid;    -   Hoveyda's Cat. for Dichloro(o-isopropoxyphenylmethylene)        (tricyclohexylphosphine)ruthenium(II);    -   In for indium;    -   KHMDS is potassium bis(trimethylsilyl) amide;    -   Ms for mesyl;    -   NMM for N-4-methylmorpholine;    -   NMO for N-4-methylmorpholine-N-Oxide;    -   PyBrOP for Bromo-tri-pyrolidino-phosphonium hexafluorophosphate;    -   Ph for phenyl;    -   RCM for ring-closing metathesis;    -   RT for reverse transcription;    -   RT-PCR for reverse transcription-polymerase chain reaction;    -   TBME for tert-butyl methyl ether;    -   TEA for triethyl amine;    -   TFA for trifluoroacetic acid;    -   THF for tetrahydrofuran;    -   TLC for thin layer chromatography;    -   TPAP tetrapropylammonium perruthenate;    -   TPP or PPh₃ for triphenylphosphine;    -   tBOC or Boc for tert-butyloxy carbonyl;    -   Xantphos for        4,5-Bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene; and    -   Zhan 1 B for

Synthetic Methods

The compounds and processes of the present invention will be betterunderstood in connection with the following synthetic schemes thatillustrate the methods by which the compounds of the invention may beprepared, which are intended as an illustration only and not to limitthe scope of the invention. Various changes and modifications to thedisclosed embodiments will be apparent to those skilled in the art andsuch changes and modifications including, without limitation, thoserelating to the chemical structures, substituents, derivatives, and/ormethods of the invention may be made without departing from the spiritof the invention and the scope of the appended claims.

The preparation of quinoxalinyl macrocyclic compounds is exemplified inScheme 1. The Boc group of quinoxaline derivative 1-1 (see Scheme 2 forpreparation) was deprotected under acidic condition at room temperature(the acid can be selected from, but not limited to, HCl in dioxane orHCl in ethyl acetate or TFA. For further details on deprotection of Bocgroup see: T. W. Greene, Protective Groups in Organic Synthesis, FourthEdition, John Wiley and Sons, 2006) to give the amine 1-2, which iscoupled with acid 1-3 employing peptide coupling reagent (the couplingreagent can be selected from, but not limited to, HATU/DIPEA, DCC/DMAP,for further details on peptide coupling reagents see: Christian A. G. N.Montalbetti et al., Tetrahedron 2005, 61, 10827) to afford the diene1-4. Ring-closing metathesis of diene 1-4 with a ruthenium-basedcatalyst gives the desired macrocyclic alkene 1-5 (for further detailson ring-closing metathesis see recent reviews: Grubbs et al., Acc. Chem.Res., 1995, 28, 446; Shrock et al., Tetrahedron 1999, 55, 8141;Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3012; Trnka et al., Acc.Chem. Res. 2001, 34, 18, and Hoveyda et al., Chem. Eur. J. 2001, 7,945).

Wherein R′, R, G and

are previously defined as in Formula I.

The hydrolysis of the macrocyclic ester 1-5 to the corresponding acid1-6 could be effected with inorganic base, such as, but not limited toLiOH, NaOH, KOH. The resulted acid 1-6 is coupled with amine 1-7employing amide coupling reagent (the coupling reagent can be selectedfrom, but not limited to, HATU, DCC and HOBT in the presence of organicbase such as, but not limited to, DIEPA, TEA, DMAP; for further detailson amide formation see recent review: Christian A. G. N. Montalbetti etal., Tetrahedron 2005, 61, 10827) to afford amide 1-8 or 1-9.Alternatively, amide 1-8 can be prepared from the acid 1-10, which issynthesized from the hydrolysis of the ester 1-8. The acid 1-9 wasactivated with CDI and followed by coupling with sulfonamide 1-11 inpresence of organic base such as, but not limited to DBU to provide thetitle compound 1-8.

The synthesis of quinoxaline derivative 1-1 is exemplified in Scheme 2.The bromide 2-2 was coupled with aldehyde 2-1 employing metal such as,but not limited to In, Zn, Mg or Cr to afford the hydroxyl ester 2-3,which was further oxidized to give the ketone ester 2-4 with oxidationreagent such a, but not limited to TPAP/NMO. Alternatively, thesynthesis of ketone ester 2-4 could be effected through lithium halogenexchange of bromide 2-2 followed by coupling with ester 2-5 (thisprecedure could also be applied to acid chloride 2-6 or the Weinrebamide 2-7) to afford the ketone ester 2-4. Yet another alternativeprocedure is that the bromide 2-2 was treated with metal such as, butnot limited to In, Zn or Mg and then reacted with acid chloride 2-6 orester 2-5 or Weinreb amide 2-7 to give the ketone ester 2-4. The ketoneester 2-4 was condensed with diamine 2-8 to afford the quinoxaline 2-9.The hydroxyl quinoxaline 2-9 was converted into chloroquinoxaline 3-3utilizing chlorination reagent such as but not limited to, POCl₃, whichwas coupled with commercially available N-Boc-trans-4-hydroxy-L-proline2-11 and followed by esterification to give the quinoxaline derivative1-1. Alternatively, compound 1-1 could be synthesized from the Mitsunobureaction of commercially available alcohol 2-12 with quinoxaline 2-9.For further details on the Mitsunobu reaction, see O. Mitsunobu,Synthesis 1981, 1-28; D. L. Hughes, Org. React. 1983, 29, 1; D. L.Hughes, Organic Preparations and Procedures Int. 1996, 28, 127; and J.A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1997, 1, 273; K. C.Kumara Swamy et. al., Chem. Rev. 2009, 109, 2551.

wherein

is previously defined as in Formula I.

The synthesis of acid 1-3 commenced with acylation of the racemic diol3-1 to afford the diacetate 3-2 (for hydroxyl acylation see: T. W.Greene, Protective Groups in Organic Synthesis, Fourth Edition, JohnWiley and Sons, 2006). The kinetic resolution of the diacetate 3-2 wasachieved by partial deacetylation with enzyme such as, but not limitedto, Amano lipase to give the mono acetate 3-3 (M. P. Schneider et al.,J. Chem. Soc., Chem. Commun., 1991, 49; for further information onkinetic resolution see: H. Pellissier, Tetrahedron, 2008, 64, 1563).

Allylation of monoacetate compound 3-3 affords allyl ether 3-4, whichwas hydrolyzed with inorganic base such as, but not limited to, LiOH,NaOH to afford the alcohol 3-5. Upon the chloroformation by treatingalcohol 3-5 with COCl₂, followed by coupling with amino acid 3-6 toprovide the acid 1-3. Moreover, the allyl ether 3-5 could also beobtained when optical pure diol 3-1 was deprotonated with NaH followedby coupling with allyl bromide.

wherein R′ and

are previously defined as in Formula I.

The alternative routes for synthesis of macrocyclic ester 1-5 have beenexemplified in Scheme 4. There are many other synthetic routes to thisintermediate 1-5, some precursors are shown in Scheme 4. For example,the macrocyclic ester 1-5 could be obtained via the amide bond formationin acid 4-1 (for further details on amide bond formation see recentreview: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61,10827); Pd catalyzed intramolecular allylation in allylic Boc derivative4-2 (Guoqiang Wang et al., Org. Lett., 2004, 6, 4455); the deprotectionof Boc group (for carbamate deprotection see: T. W. Greene, ProtectiveGroups in Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006)followed by carbamate formation in succinimidyl carbonate 4-3 (J. V.Eycken, J. Org. Chem., 2007, 72, 5514); base catalyzed ether formationin alcohol 4-4 and Mitsunobu type ether formation in hydroxylquinoxaline 4-5 (for further details on the Mitsunobu reaction, see O.Mitsunobu, Synthesis 1981, 1-28; D. L. Hughes, Org. React. 1983, 29, 1;D. L. Hughes, Organic Preparations and Procedures Int. 1996, 28, 127;and J. A. Dodge, S. A. Jones, Recent Res. Dev. Org. Chem. 1997, 1, 273;K. C. Kumara Swamy et. al., Chem. Rev. 2009, 109, 2551).

wherein

is previously defined as in Formula I.

The synthesis of acid 4-1 has been exemplified in Scheme 5. Thecross-metathesis of quinoxaline derivative 1-1 and allyl ether 3-5 leadsto the alcohol 5-1 (for further details on cross metathesis see: Grubbset al. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett.2006, 8, 2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45). Thisalcohol 5-1 was treated with phosgene (or some other reagent such as,but not limited to triphosgene, diphosgene, carbonyldiimidazole)followed by coupling with amino acid 3-6 in the present of base such as,but not limited to LiOH or NaOH. The deprotection of Boc group in acid5-2 (for carbamate deprotection see: T. W. Greene, Protective Groups inOrganic Synthesis, Fourth Edition, John Wiley and Sons, 2006) affordsthe acid 4-1.

wherein R, R″ and

are previously defined as in Formula I.

The synthesis of quinoxalinyl derivative 4-3 has been exemplified inScheme 6. The deprotection of Boc group (T. W. Greene, Protective Groupsin Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) inester 5-1 provides the corresponding amine, which is coupled with aminoacid 6-1 utilizing peptide coupling reagent such as, but not limited toHATU, or DCC or BOP (for further details on peptide coupling see:Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827) toafford the alcohol 6-2. The activation of hydroxyl group in alcohol 6-2is achieved when treated with DSC/TEA to afford the succinimidylcarbonate 4-3 (for application of DSC in carbamate formation see: J. V.Eycken, J. Org. Chem., 2007, 72, 5514).

wherein R, R″ and

are previously defined as in Formula I.

The synthesis of quinoxalinyl derivative 4-2 has been exemplified inScheme 7. The deprotection of Boc group (T. W. Greene, Protective Groupsin Organic Synthesis, Fourth Edition, John Wiley and Sons, 2006) ofester compound 1-1 provides the corresponding acid, which is coupledwith amino acid 6-1 utilizing peptide coupling reagent such as, but notlimited to HATU, or DCC or BOP (for further details on peptide couplingsee: Christian A. G. N. Montalbetti et al., Tetrahedron 2005, 61, 10827)to afford the alcohol 7-1. The Boc group in compound 7-1 was removedunder acidic condition and the resulted amine was treated with phosgeneor other reagent such as, but not limited to triphosgene or diphosgeneor carbonyldi-imidazole in the presence of base such as, but not limitedto pyridine or DMAP to afford the isocyanate 7-2. This isocyanate 7-2was coupled with diol 7-3 in the presence of organic base such as, butnot limited to DBU to provide the mono alcohol 7-4. Cross metathesis ofalkene 7-4 and protected diol 7-5 in the presence of catalyst providesthe alcohol 4-2 (for further details on cross metathesis see: Grubbs etal. J. Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006,8, 2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45).

wherein R, R″ and

are previously defined as in Formula I.

The synthesis of quinoxalinyl derivative 4-4 has been exemplified inScheme 8. The alcohol 3-5 is treated with phosgene or other reagent suchas, but not limited to triphosgene or diphosgene or carbonyldi-imidazoleand then coupled with amine 8-1 in the presence of base such as, but notlimited to NaOH to afford the alkene 8-2, which will undergo crossmetathesis with quinoxalinyl derivative 2-10 to provide the t-butylester 8-3 (for further details on cross metathesis see: Grubbs et al. J.Am. Chem. Soc. 2003, 125, 11360; R. Raju et al. Org. Lett. 2006, 8,2139; Y. Schrodi et al. Aldrichimica Acta 2007, 40, 45). The t-butylgroup in compound 8-3 was deprotected under acidic condition (the acidis selected from, but not limited to HCl or TFA) and this is followed bycoupling with amine 8-4 utilizing peptide coupling reagents (for furtherdetails on peptide coupling see: Christian A. G. N. Montalbetti et al.,Tetrahedron 2005, 61, 10827) to afford the quinoxalinyl compound 4-4.

wherein R and

is previously defined as in Formula I.

The synthesis of quinoxalinyl derivative 4-5 has been exemplified inScheme 9. Analogous to the synthesis of intermediate 8-3, the crossmetathesis of t-butyl ester 8-2 and quinoxalinyl derivative 2-9 providesthe t-butyl ester 9-1. The removal of t-butyl group in 9-1 could beachieved under acidic condition (HCl) to afford the acid 9-2, whichundergoes coupling with amine 9-3 employing peptide coupling reagentsuch as, but not limited to HATU/DIPEA to provide the intermediate 4-5.

EXAMPLES

The compounds and processes of the present invention will be betterunderstood in connection with the following examples, which are intendedas an illustration only and not to limit the scope of the invention.Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art and such changes and modificationsincluding, without limitation, those relating to the chemicalstructures, substituents, derivatives, formulations and/or methods ofthe invention may be made without departing from the spirit of theinvention and the scope of the appended claims.

Example 1

Compound of Formula VIII, wherein

Step 1a

To the solution of 3-bromo-3,3-difluoroprop-1-ene 2-2 (5.61 g, 35.74mmol) and ethyl glyoxalate 2-1 (6.52 ml, 42.9 mmol, 50% in toluene) inDMF (80 ml) and water (20 ml) was added Indium powder. The resultedmixture was stirred vigorously for 6 h, and then diluted with TBME, themixture was filtered and washed with water, brine, dried andconcentrated in vacuo to afford the crude product 2-3 (6.21 g). Thismaterial was used directly to next step without further purification.

To the crude ethyl 3,3-difluoro-2-hydroxypent-4-enoate 2-3 (4.9 g, 27.20mmol) in DCM (150 ml) was added TPAP (240 mg, 0.68 mmol) and NMO (11.03g, 81.61 mmol). The suspension was stirred at rt for 5h, and thendiluted with DCM, washed with water, brine, dried and concentrated invacuo to afford the crude ketone ester 2-4. This material was useddirectly to next step without further purification.

Step 1b

To the solution of crude ethyl 3,3-difluoro-2-oxopent-4-enoate 2-4(prepared from 35.74 mmol of 3-bromo-3,3-difluoroprop-1-ene) in EtOH(200 ml) was added o-benzene-1,2-diamine 2-8 (4.64 g, 42.89 mmol). Theresulted mixture was heated to reflux for 14 h and then cool down to rt,the solid was collected by filtration and washed with cold EtOH to givequinoxaline 2-9 (2.81 g) after drying. The filtrate was concentrated invacuo and the residue was purified by flash chromatography on CombiFlashwith Hexane to 30% acetone in hexane to afford another portion ofquinoxaline 2-9 (0.43 g). MS (ESI): m/z=223.09 [M+H].

Step 1c

To 3-(1,1-difluoroallyl)quinoxalin-2-ol 2-9 (2.31 g, 10.40 mmol) wasadded POCl₃ (10.8 ml) and DMF (1.1 ml), the resulted mixture was heatedto 65° C. for 2 h. The mixture was diluted with ethyl acetate and thenslowly poured into ice. After partition the organic layer was washedwith water, NaHCO₃ solution and brine to give the desired product 2-10(2.45 g). This material was used directly to next step without furtherpurification. MS (ESI): m/z=241.01 [M+H].

Step 1d

To a solution of N-Boc-trans-4-hydroxy-L-proline 2-11 (2.404 g, 10.396mmol) in DMF (14 ml) and THF (60 ml) at 0° C. was added t-BuONa (3.0 g,31.189 mmol) portionwise. The reaction mixture was allowed to warm up tort. After stirring for 1 h, the mixture was cooled down to 0° C. and2-chloro-3-(1,1-difluoroallyl)quinoxaline 2-10 (2.45 g, -10.396 mmol)was added and warmed up to rt. After stirring for 4 h, the reactionmixture was quenched with 1 N HCl at 0° C. The aqueous layer wasextracted with EtOAc (3×), and the organic layer was combined, washedwith water, brine, dried and concentrated in vacuo. To the residue inDCM (50 ml) and MeOH (10 ml) was added TMSCHN₂ (10.4 ml, 20.792 mmol,2.0 M in Hexane). The solution was stirred at rt for 30 min thenconcentrated in vacuo. The residue was purified by flash chromatographyon CombiFlash with Hexane to 30% ethyl acetate in hexane to afforddesired product 1-1 (3.84 g, 82%). MS (ESI): m/z=450.24 [M+H].

Step 1e

To a solution of (+)-cyclopentane-1,2-diol 3-1a (10.02 g, 97.159 mmol)in DCM (20 ml) and pyridine (150 ml) was added acetic anhydride (36.7ml, 388.63 mmol) and DMAP (593 mg) portionwise. The resulted solutionwas stirred for 21 h, and solvent was removed in vacuo. The residue wasdissolved in EtOAc, and the resulted solution was washed with 1N HCl,water, NaHCO₃, water and brine. The organic layer was dried andconcentrated in vacuo. The residue was purified by flash chromatographyon CombiFlash with Hexane to 15% acetone in hexane to afford thediacetate 3-2a (17.1 g, 94%).

To the suspension of (+)-cyclopentane-1,2-diyl diacetate 3-2a (17.0 g,91.3 mmol) in buffer (pH=7, 140 ml) was added Amano Lipase PS (fromBurkholderia cepacia, Aldrich, 1.81 g). The resulted mixture wasvigorously stirred and 1 N NaOH (65 ml) was added via an addition funnelover 18 h to keep the pH at 7. The mixture was diluted with EtOAc andwater, filtered and the aqueous layer was extracted with EtOAc. Theorganic layer was combined, washed with water, brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by flash chromatographyon CombiFlash with Hexane to 35% acetone in hexane to afford desiredproduct 3-3a (4.6 g, 35%).

To a solution of (1R,2R)-2-hydroxycyclopentyl acetate 3-3a (3.42 g,23.715 mmol) in DMF (80 ml) at 0° C. was added NaH (1.04 g, 26.087 mmol,60% dispersion in mineral oil). The resulted mixture was warmed up to rtand stirred for 30 min, and it was cooled down to 0° C. and allylbromide (2.2 ml, 26.087 mmol) was added. The mixture was stirred at rtfor 1.5 h and quenched with NH₄Cl solution at 0° C. The mixture wasextracted with EtOAc (3×), and the organic layer was combined, washedwith water, brine, dried (Na₂SO₄) and concentrated in vacuo. To theresidue in MeOH (47 ml) and THF (94 ml) was added 1 N LiOH solution(47.4 ml, 47.43 mmol). The mixture was stirred for 30 min and themixture was extracted with EtOAc (3×), and the organic layer wascombined, washed with water, brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography on CombiFlashwith Hexane to 25% acetone in hexane to afford alcohol 3-5a (1.36 g,40%, 95.8% ee by HPLC).

Step 1f

To a solution of (1R,2R)-2-(allyloxy)cyclopentanol 3-5a (2.20 g, 15.50mmol) in THF (150 ml) was added phosgene solution (16.3 ml, 30.9 mmol,20% in toluene). The resulted solution was stirred for 14 h, andconcentrated in vacuo. To the residue in dioxane (50 ml) was addedL-tert-leucine 3-6a (2.237 g, 17.05 mmol) in dioxane (100 ml) and 1 NNaOH (18.6 ml, 18.6 mmol). The mixture was stirred for 5 h, andacidified with 1N HCl. The mixture was extracted with EtOAc (3×), andthe organic layer was combined, washed with water, brine, dried andconcentrated in vacuo to afford the acid 1-3a (4.32 g). This materialwas used directly to next step without further purification.

Step 1g

To a solution of quinoxaline derivative 1-1 (3.02 g, 6.719 mmol) in DCM(20 ml) was added 4 N HCl (20 ml, in dioxane). The resulted solution wasstirred for 2 h and solvent was removed in vacuo. To the residue in DMF(67 ml) was added acid 1-3a (1.849 g, 8.063 mmol), HATU (3.321 g, 8.735mmol) and DIPEA (2.33 ml, 13.438 mmol). The mixture was stirred for 3 hand concentrated in vacuo. The residue was dissolved in EtOAc and washedwith 1 N HCl (2×), water, brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography on CombiFlashwith Hexane to 35% EtOAc in hexane to afford diene 1-4a (2.48 g, 59%).MS-ESI m/z 631.43 (M+H)⁺.

Step 1h

To a solution of the diene 1-4a (1.38 g, 2.188 mmol) in toluene undernitrogen atmosphere at 110° C. was added Zhan 1B catalyst (128 mg, 0.140mmol) and the resulted solution was stirred at 110° C. for 37 h. Zhan 1Bcatalyst (70 mg×2) was added in two portions and the reaction wasstopped until the disappearance of starting material by MS. The mixturewas concentrated in vacuo and the residue was purified by flashchromatography on CombiFlash with Hexane to 40% EtOAc in hexane toafford the alkene 1-5a (0.768 g, 59%). MS-ESI m/z 603.20 (M+H)⁺.

Step 1i

To a solution of the ester 1-5a (1.38 g, 2.29 mmol) in MeOH (23 ml) andTHF (46 ml) was added LiOH solution (22.9 ml, 1 N). The resulted mixturewas stirred for 16 h and quenched with 1 N HCl. The mixture wasextracted with DCM (3×), and the organic layer was combined, washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to afford the acid 1-6a.The acid was used to the next step without further purification.

Step 1j

The acid 1-6a (crude product from step 1i) was dissolved in DCM (70 ml),and to this solution was added sulfonamide 1-7a (702 mg, 2.404 mmol),HATU (1.045 g, 2.748 mmol) and DIPEA (0.60 ml, 3.435 mmol). The mixturewas stirred for 3 h, and then diluted with DCM. The organic layer waswashed with 1 N HCl, water, brine, dried and concentrated in vacuo. Theresidue was first purified by flash chromatography on CombiFlash withHexane to 50% EtOAc in hexane and then further purified by HPLC toafford the title compound (1.126 g, 60%). MS-ESI m/z 801.40 (M+H)⁺.

Example 2

Compound of Formula VIII, wherein

Step 2a

The acid 1-6a (19.5 mg, 0.0332 mmol) was dissolved in DCM (1.0 ml), andto this solution was added sulfonamide 1-7b (13.2 mg, 0.0432 mmol), HATU(18.9 mg, 0.0498 mmol) and DIPEA (11.5 ul, 0.0664 mmol). The mixture wasstirred for 3 h, and then diluted with DCM. The organic layer was washedwith 1 N HCl, water, brine, dried and concentrated in vacuo. The residuewas purified by HPLC to afford the title compound. MS-ESI m/z 825.39(M+H)⁺.

Example 4

Compound of Formula VIII, wherein

Step 4a

The acid 1-6a (21 mg, 0.0356 mmol) was dissolved in DCM (1.5 ml), and tothis solution was added sulfonamide 1-7c (12.4 mg, 0.0463 mmol), HATU(17.6 mg, 0.0462 mmol) and DIPEA (12.4 ul, 0.0712 mmol). The mixture wasstirred for 3 h, and then diluted with DCM. The organic layer was washedwith 1 N HCl, water, brine, dried and concentrated in vacuo. The residuewas purified by HPLC to afford the title compound. MS-ESI m/z 803.25(M+H)⁺.

Example 5

Compound of Formula VIII, wherein

Step 5a

The acid 1-6a (19.5 mg, 0.0332 mmol) was dissolved in DMF (0.5 ml) andDCM (0.5 ml), and to this solution was added sulfonamide 1-7d (13.8 mg,0.0465 mmol), HATU (18.9 mg, 0.0498 mmol) and DIPEA (11.5 ul, 0.0664mmol). The mixture was stirred for 2 h and the solvent was removed invacuo, the residue was purified by HPLC to afford the title compound.MS-ESI m/z 815.38 (M+H)⁺.

Example 6

Compound of Formula VIII, wherein

Step 6a

The acid 1-6a (21 mg, 0.0356 mmol) was dissolved in DCM (1.5 ml), and tothis solution was added sulfonamide 1-7e (13.0 mg, 0.0463 mmol), HATU(17.6 mg, 0.0462 mmol) and DIPEA (12.4 ul, 0.0712 mmol). The mixture wasstirred for 3 h, and then diluted with DCM. The organic layer was washedwith 1 N HCl, water, brine, dried and concentrated in vacuo. The residuewas purified by HPLC to afford the title compound. MS-ESI m/z 839.41(M+H)⁺.

Example 8

Compound of Formula VIII, wherein

Step 8a

The acid 1-6a (19.5 mg, 0.0332 mmol) was dissolved in DMF (0.5 ml) andDCM (0.5 ml), and to this solution was added sulfonamide 1-7f (13.8 mg,0.0465 mmol), HATU (18.9 mg, 0.0498 mmol) and DIPEA (11.5 ul, 0.0664mmol). The mixture was stirred for 2 h and the solvent was removed invacuo, the residue was purified by HPLC to afford the title compound.MS-ESI m/z 817.37 (M+H)⁺.

Example 34

Compound of Formula VIII, wherein

Step 34a

A mixture of compound 34a-1 (2.0 g, 8.678 mol), Pd/C (458 mg, 0.434mmol, 10% wet) and THF (100 ml) was hydrogenated under 60 PSI for 15 h,and another portion of Pd/C (458 mg) was added, the mixture was stirredfor another 20 h until the disappearance of starting material. Themixture was filtered, washed with ethyl acetate. The filtrate wasconcentrated in vacuo and the residue was purified by flashchromatography on CombiFlash with Hexane to 60% EtOAc in hexane toafford the diol 34a-2 (315 mg, 41%).

To the solution of diol 34a-2 (400 mg, 4.545 mmol) in DMF (8 ml) at 0°C. was added NaH (200 mg, 5.0 mmol, 60% dispersion in mineral oil). Theresulted mixture was warmed up to rt and stirred for 40 min, the allylbromide (0.42 ml, 5.0 mmol) was added. The mixture was stirred for 2 h,and quenched with NH₄Cl solution. The mixture was diluted with ethylacetate, washed with water, brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography on CombiFlashwith Hexane to 25% acetone in hexane to afford the alcohol 34a-3 (132mg).

To the solution of alcohol 34a-3 (132 mg, 1.031 mmol), PPh₃ (810.9 mg,3.092 mmol) and 4-nitrobenzoic acid (586 mg, 3.505 mmol) in THF (10 ml)was added DIAD (0.61 ml, 3.092 mmol). The resulted solution was stirredfor 11 h, and the solvent was removed in vacuo. The residue was purifiedby flash chromatography on CombiFlash with Hexane to 40% EtOAc in hexaneto afford the ester 34a-4 (161 mg, 56%).

To the solution of alcohol 34a-4 (161 mg, 0.581 mmol) in THF (4 ml) andMeOH (2 ml) was added LiOH (2 ml, 1 N). The mixture was stirred for 2.5h and the mixture was extracted with EtOAc (3×). The organic layer wascombined, washed with water, brine, dried (Na₂SO₄) and concentrated invacuo to afford the alcohol 34a-5 (58 mg). This material was useddirectly to the next step without further purification.

Step 34b

To a solution of (1R,2R)-2-(allyloxy)cyclobutanol 34a-5 (58 mg, 0.453mmol) in THF (2 ml) was added phosgene solution (0.48 ml, 0.906 mmol,20% in toluene). The resulted solution was stirred for 4 h, andconcentrated in vacuo. To the residue in dioxane (5 ml) was addedL-tert-leucine 3-6a (71 mg, 0.544 mmol) and 1 N NaOH (0.59 ml, 0.59mmol). The mixture was stirred for 14 h, and acidified with 1N HCl. Themixture was extracted with EtOAc (3×), and the organic layer wascombined, washed with water, brine, dried and concentrated in vacuo toafford the acid 1-3b (117 mg). This material was used directly to nextstep without further purification.

Step 34c

To a solution of quinoxaline derivative 1-1 (224 mg, 0.498 mmol) in DCM(2 ml) was added HCl (3 ml, 4 N in dioxane). The resulted solution wasstirred for 1.5 h and solvent was removed in vacuo. To the residue inDCM (8 ml) was added acid 1-3b (120 mg, 0.453 mmol), HATU (258 mg, 0.680mmol) and DIPEA (0.17 ml, 0.996 mmol). The mixture was stirred for 3 hand concentrated in vacuo. The residue was dissolved in EtOAc and washedwith 1 N HCl (2×), water, brine, dried (Na₂SO₄) and concentrated invacuo. The residue was purified by flash chromatography on CombiFlashwith Hexane to 35% EtOAc in hexane to afford diene 1-4b (115 mg). MS-ESIm/z 617.3 (M+H)⁺.

Step 34d

To a solution of the diene 1-4b (115 mg, 0.186 mmol) in toluene undernitrogen atmosphere at 110° C. was added Zhan 1B catalyst (14 mg, 0.0186mmol) and the resulted solution was stirred at 110° C. for 19 h. Themixture was concentrated in vacuo and the residue was purified by flashchromatography on CombiFlash with Hexane to 35% EtOAc in hexane toafford the alkene 1-5b (38 mg). MS-ESI m/z 589.25 (M+H)⁺.

Step 34e

To a solution of the ester 1-5b (38 mg, 0.0646 mmol) in MeOH (1 ml) andTHF (2 ml) was added LiOH solution (1 ml, 1 N). The resulted mixture wasstirred for 14 h and quenched with 1 N HCl. The mixture was extractedwith ethyl acetate (3×), and the organic layer was combined, washed withbrine, dried (Na₂SO₄) and concentrated in vacuo to afford the acid 1-6b.The acid was used to the next step without further purification. MS-ESIm/z 575.27 (M+H)⁺.

Step 34f

Following procedure described in the preparation of example 2 (step 2a),acid 1-6b was converted to compound example 34. MS-ESI m/z 833.40(M+H)⁺.

Example 36

Compound of Formula VIII, wherein

Following procedure described in the preparation of example 4 (step 4a),acid 1-6b was converted to compound example 36. MS-ESI m/z 789.45(M+H)⁺.

Example 40

Compound of Formula VIII, wherein

Following procedure described in the preparation of example 8 (step 8a),acid 1-6b was converted to compound example 40. MS-ESI m/z 803.47(M+H)⁺.

Example 265

Compound of Formula X, wherein

Step 265a

To a suspension of NaH (49 mg, 1.22 mmol, 60% in mineral oil) in THF wasadded a solution of 2-1-1 (0.1 g, 0.489 mmol) in THF (1.5 mL) at 0° C.After stirred at 0° C. for 45 min, a solution of2-chloro-3-(1,1-difluoroallyl)quinoxaline 2-10 in THF (1 mL) was addedand then the reaction mixture was heated at 60° C. for 3 h. Cooled to 0°C. and quenched with 2 N HCl at 0° C. The aqueous layer was extractedwith DCM (3×), and the organic layer was combined, washed with water,brine, dried and concentrated in vacuo. To the residue in MeOH (5 ml)was added TMSCHN₂ (2 mL, 4 mmol, 2.0 M in Hexane) and the solution wasstirred at rt for 30 min. Concentrated in vacuo. The residue waspurified by flash chromatography with Hexane to 40% ethyl acetate inhexane to afford desired product 1-1-1 (82 mg, 43%). MS (ESI):m/z=464.21 [M+H].

Step 265b

To a solution of quinoxaline derivative 1-1-1 (82 mg, 0.18 mmol) in DCM(3 mL) was added 4 N HCl (12 mL, in dioxane). The resulted solution wasstirred for 2 h at 0° C. and solvent was removed in vacuo. To theresidue in DCM (2 mL) was added acid 1-3a (69 mg, 0.23 mmol), HATU(133.8 mg, 0.352 mmol) and DIPEA (122.6 μL, 0.704 mmol). The mixture wasdiluted in DCM and washed with 10% citric acid, sat. NaHCO₃, brine,dried (Na₂SO₄) and concentrated in vacuo. The residue was purified byflash chromatography with Hexane to 40% EtOAc in hexane to afford diene1-4-1 (129.5 mg, >99%). MS-ESI m/z 645.33 (M+H)⁺.

Step 265c

To a solution of the diene 1-4-1 (110 mg, 0.17 mmol) in toluene undernitrogen atmosphere at 110° C. was added Zhan 1B catalyst (17.9 mg,0.026 mmol) and the resulted solution was stirred at 110° C. for 5 h.The mixture was concentrated in vacuo and the residue was purified byflash chromatography with Hexane to 40% EtOAc in hexane to afford thealkene 1-5-1 (38 mg, 36%). MS-ESI m/z 617.32 (M+H)⁺.

Step 265d

To a solution of the ester 1-5-1 (38 mg, 0.062 mmol) in MeOH (3 mL) andTHF (6 mL) was added LiOH solution (3 mL, 1 N). The resulted mixture wasstirred for 9 h at 0° C.˜rt and quenched with 1 N HCl at 0° C. Themixture was extracted with DCM (3×), and the organic layer was combined,washed with brine, dried (Na₂SO₄) and concentrated in vacuo to affordthe acid 1-6-1. The acid was used to the next step without furtherpurification.

Step 265e

The acid 1-6-1 (9.8 mg, 0.0166 mmol) was dissolved in DCM (1.0 mL), andto this solution was added sulfonamide 1-7a (6.2 mg, 0.0216 mmol), HATU(9.5 mg, 0.0216 mmol) and DIPEA (5.8 μL, 0.0249 mmol). The mixture wasstirred for 3 h, and then diluted with DCM. The organic layer was washedwith with 10% citric acid, sat. NaHCO₃, brine, dried (Na₂SO₄) andconcentrated in vacuo. The residue was purified by preparative TLC 50%EtOAc in hexane afford the title compound (2.0 mg, 20%). MS-ESI m/z815.30 (M+H)⁺.

Example 266

Compound of Formula X, wherein

Step 266a

The acid 1-6-1 (crude product from step 266d) was dissolved in DCM (1mL), and to this solution was added sulfonamide 1-7b (10.2 mg, 0.035mmol), HATU (13.3 mg, 0.035 mmol) and DIPEA (12.2 μL, 0.07 mmol). Themixture was stirred for 3 h, and then diluted with DCM. The organiclayer was washed with with 10% citric acid, sat. NaHCO₃, brine, dried(Na₂SO₄) and concentrated in vacuo. The residue was purified bypreparative TLC 50% EtOAc in hexane afford the title compound (3 mg,30%). MS-ESI m/z 839.38 (M+H)⁺.

Example 268

Compound of Formula X, wherein

Step 268a

The acid 1-6-1 was dissolved in DCM (1 mL), and to this solution wasadded sulfonamide 1-7c (12.4 mg, 0.0463 mmol), HATU (17.6 mg, 0.0462mmol) and DIPEA (12.4 uL, 0.0712 mmol). The mixture was stirred for 3 h,and then diluted with DCM. The organic layer was washed with 10% citricacid, sat. NaHCO₃, brine, dried (Na₂SO₄) and concentrated in vacuo. Theresidue was purified by preparative TLC 50% EtOAc in hexane afford thetitle compound (2.6 mg, 25%). MS-ESI m/z 816.91 (M+H)⁺.

Example 273

Compound of Formula XI, wherein

Step 273a

To the solution of ethyl 3,3-difluoro-2-oxopent-4-enoate 2-4 (0.417 g,2.34 mmol) in EtOH (12 ml) was added 2-amino-4-(trifluoromethoxy)aniline2-8-1 0.54 g, 2.81 mmol). The resulted mixture was heated to reflux for14 h and then cool down to rt, the mixture was diluted by ethyl acetate,washed by 1M HCl, water, and brine. The solvent was removed and thecrude product was purified by combiflash (12 g silica gel, 0-50% EA inHexanes) to give 2-9-1 (0.228 g, 0.745 mmol, 31.8% yield) and 2-9-2(0.358 g, 1.169 mmol, 49.9% yield).

Step 273b

To the solution of 2-9-2 (0.228 g, 0.745 mmol), (2S,4S)-1-tert-butyl2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (0.219 g, 0.894 mmol)and Triphenylphosphine (0.293 g, 1.117 mmol) in THF (3.72 ml), theDiisopropyl azodicarboxylate (0.217 ml, 1.117 mmol) was added dropwiseat room temperature. The mixture was stirred at room temperature for 2h. The mixture was concentrated. The crude product was purified bycombiflash (25 g silica gel, 0-40% ethyl acetate in Hexanes) to give1-1-1 (0.320 g, 0.600 mmol, 81% yield). MS-ESI, m/z=534.45 (M+1)⁺.

Step 273c

The compound 1-4a-1 was prepared by following the procedure described inthe preparation of example 1 (step 1g). MS-ESI m/z 715.3 (M+H)⁺.

Step 273d

The compound 1-5a-1 was prepared by following the procedure described inthe preparation of example 1 (step 1h). MS-ESI m/z 687.4 (M+H)⁺.

Step 273e

The compound 1-6a-1 was prepared by following the procedure described inthe preparation of example 1 (step 1i). MS-ESI m/z 673.3 (M+H)⁺.

Step 273f

The compound of example 273 was prepared by following the proceduredescribed in the preparation of example 1 (step 1j). MS-ESI m/z 923.4(M+H)⁺.

Example 274

Compound of Formula XI, wherein

The compound of example 274 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 899.3 (M+H)⁺.

Example 275

Compound of Formula XI, wherein

The compound of example 275 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 923.4 (M+H)⁺.

Example 276

Compound of Formula XI, wherein

The compound of example 276 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 899.3 (M+H)⁺.

Example 277

Compound of Formula XI, wherein

The compound of example 277 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 833.4 (M+H)⁺.

Example 278

Compound of Formula XI, wherein

The compound of example 278 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 831.4 (M+H)⁺.

Example 279

Compound of Formula XI, wherein

The compound of example 279 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 855.4 (M+H)⁺.

Example 280

Compound of Formula XI, wherein

The compound of example 280 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 847.4 (M+H)⁺.

Example 281

Compound of Formula XI, wherein

The compound of example 281 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 845.4 (M+H)⁺.

Example 282

Compound of Formula XI, wherein

The compound of example 282 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 869.4 (M+H)⁺.

Example 283

Compound of Formula XI, wherein

The compound of example 283 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 906.3 (M+H)⁺.

Example 284

Compound of Formula XI, wherein

The compound of example 284 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 883.4 (M+H)⁺.

Example 285

Compound of Formula XI, wherein

The compound of example 285 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 893.3 (M+H)⁺.

Example 286

Compound of Formula XI, wherein

The compound of example 286 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 883.4 (M+H)⁺.

Example 287

Compound of Formula XI, wherein

The compound of example 287 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 868.4 (M+H)⁺.

Example 288

Compound of Formula XI, wherein

The compound of example 288 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 831.4 (M+H)⁺.

Example 289. Compound of Formula XI, wherein

The compound of example 289 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 845.4 (M+H)⁺.

Example 290

Compound of Formula XI, wherein

The compound of example 290 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 889.4 (M+H)⁺.

Example 291

Compound of Formula XI, wherein

The compound of example 291 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 865.4 (M+H)⁺.

Example 292

Compound of Formula XI, wherein

The compound of example 292 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 889.4 (M+H)⁺.

Example 293

Compound of Formula XI, wherein

The compound of example 293 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 865.4 (M+H)⁺.

Example 294

Compound of Formula XI, wherein

The compound of example 294 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 833.4 (M+H)⁺.

Example 295

Compound of Formula XI, wherein

The compound of example 295 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 833.4 (M+H)⁺.

Example 296

Compound of Formula XI, wherein

The compound of example 296 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 857.3 (M+H)⁺.

Example 297

Compound of Formula XI, wherein

The compound of example 297 was prepared by following the proceduredescribed in the preparation of example 273. MS-ESI m/z 843.3 (M+H)⁺.

The compounds of the present invention exhibit potent inhibitoryproperties against the HCV NS3 protease. The following examples describeassays in which the compounds of the present invention can be tested foranti-HCV effects.

Example 301. Biological Assays

Each compound's anti-HCV activity can be determined by measuring theactivity of the luciferase reporter gene in the replicon in the presenceof 5% FBS. The luciferase reporter gene, and selectable marker gene forreplicons stably maintained in cell lines, is placed under thetranslational control of the poliovirus IRES instead of the HCV IRES,and HuH-7 cells are used to support the replication of the replicon.

The inhibitory activities of the compounds of the present invention canbe evaluated using a variety of assays known in the art. For instance,stable subgenomic replicon cell lines can be used for compoundcharacterization in cell culture, including those derived from genotypes1a-H77, 1b-N and 1b-Con1, obtained from University of Texas MedicalBranch, Galveston, Tex. (1a-H77 and 1b-N) or Apath, LLC, St. Louis, Mo.(1b-Con1). Chimeric replicons using the genotype 1a or 1b replicons withinsertion of NS3 genes from isolates from humans infected with genotypes1a or 1b can be used to measure inhibitory activity against a panel ofthe target protein from natural isolates. Chimeric replicons using thegenotype 1a or 1b replicons with insertion of NS3 genes from isolatesfrom humans infected with genotypes 3a, 4 or 6 can be used to measureinhibitory activity against representatives of those genotypes. Thegenotype 1a replicon construct contains the NS3-NS5B coding regionderived from the H77 strain of HCV (1a-H77). The replicon also has afirefly luciferase reporter and a neomycin phosphotransferase (Neo)selectable marker. These two coding regions, separated by the FMDV 2aprotease, comprise the first cistron of the bicistronic repliconconstruct, with the second cistron containing the NS3-NS5B coding regionwith addition of adaptive mutations E1202G, K1691R, K2040R and S22041.The 1b-Con1 and 1b-N replicon constructs are identical to the 1a-H77replicon, except that the HCV 5′ UTR, 3′ UTR, and NS3-NS5B coding regionare derived from the 1b-Con1 or 1b-N strain, and the adaptive mutationsare K1609E, K1846T and Y3005C for 1b-Con1 or A1098T, E1202G, and S22041for 1b-N. In addition, the 1b-Con1 replicon construct contains apoliovirus IRES between the HCV IRES and the luciferase gene. Repliconcell lines can be maintained in Dulbecco's modified Eagles medium (DMEM)containing 10% (v/v) fetal bovine serum (FBS), 100 IU/ml penicillin, 100mg/ml streptomycin (Invitrogen), and 200 mg/ml G418 (Invitrogen).

The inhibitory effects of the compounds of the invention on HCVreplication can also be determined by measuring activity of theluciferase reporter gene encoded by subgenomic replicons not containingthe Neo selectable marker, that are transiently expressed in cells. Theadaptive mutations encoded by the 1a-H77, 1b-N and 1b-Con-1 repliconsare the same as listed above. The 1b-Con1 replicon used for thesetransient assays contains the NS2-NS5B coding region rather than theNS3-5B coding region. These replicons may encode target NS3 genes asdescribed for stable subgenomic replicons or they may encode amino acidvariants that confer varying degrees of susceptibility to the drug. Forexample, variants could include R₁₅₅K, D168E or D168V in a genotype 1aNS3 gene; R₁₅₅K or D168V in a genotype 1b NS3 gene; S138T, A166T orQ168R in a genotype 3a NS3 gene. For example, cells can be transfectedwith the replicon by electroporation and seeded into 96 well plates at adensity of 5000 cells per well in 100 μl DMEM containing 5% FBS.Compounds diluted in dimethyl sulfoxide (DMSO) to generate a 200x stockin a series of eight half-log dilutions can then be further diluted100-fold in the medium containing 5% FBS and added to the cell cultureplates already containing 100 μl of DMEM with 5% FBS. After anincubation period of either 3 or 4 days, 30 μl of Passive Lysis buffer(Promega) can be added to each well, with incubation for 15 minutes withrocking to lyse the cells. Luciferin solution (100 al, Promega) can beadded to each well, and luciferase activity can be measured with aluminometer. The percent inhibition of HCV RNA replication can becalculated for each compound concentration and the EC₅₀ value can becalculated using nonlinear regression curve fitting to the 4-parameterlogistic equation and GraphPad Prism 4 software.

When tested using genotype 1a Huh-7 stable replicon assays, compounds ofExamples 1, 4, 5, 6, 8, 275, 276, 283, 284, 287, 288, 289, 290, 291,294, 295, 296, and 297 showed EC₅₀ values of less than 1 nM; compoundsof Examples 2, 36, 40, 65, 89, 90, 273, 274, 280, 285, 292, 293, 298,and 299 showed EC₅₀ values of from 1 to 10 nM; and compounds of Example34 showed EC₅₀ values of from 10 to 100 nM.

When tested using genotype 1b Con1 stable replicon assays, compounds ofExamples 275, 276, 283, 290, 294, 295, and 296 showed EC₅₀ values ofless than 1 nM; and compounds of Examples 1, 2, 4, 5, 6, 8, 34, 36, 40,65, 89, 90, 273, 274, 279, 280, 281, 284, 285, 287, 288, 289, 291, 292,293, 297, 298, and 299 showed EC₅₀ values of from 1 to 10 nM.

When tested using genotype 1a wild-type transient replicon assays,compounds of Examples 5, 6, 275, 276, 283, 284, 287, 288, 289, 291, 294,295, and 297 showed EC₅₀ values of less than 0.1 nM; compounds ofExamples 1, 2, 4, 8, 277, 280, 281, 282, 285, 286, 292, 293, 296, 298,and 299 showed EC₅₀ values of from 0.1 to 1 nM; and compounds ofExamples 34, 36, and 40 showed EC₅₀ values of from 1 to 10 nM.

When tested using genotype 1a R₁₅₅K transient replicon assays, compoundsof Examples 2, 5, 6, 8, 275, 276, 281, 283, 284, 287, 288, 289, 291,294, 295, 296, and 297 showed EC₅₀ values of less than 0.1 nM; compoundsof Examples 1, 4, 277, 280, 282, 285, 286, 292, 293, and 299 showed EC₅₀values of from 0.1 to 1 nM; and compounds of Examples 34, 40, 36, and298 showed EC₅₀ values of from 1 to 10 nM.

When tested using genotype 1a D168E transient replicon assays, compoundsof Examples 1, 2, 4, 5, 6, and 8 showed EC₅₀ values of less than 1 nM;and compounds of Examples 40, 298, and 299 showed EC₅₀ values of from 1to 100 nM.

When tested using genotype 1a D168V transient replicon assays, compoundsof Examples 2, 5, 6, 276, 281, 287, 288, 289, 291, 292, 295, 296, and297 showed EC₅₀ values of less than 1 nM; compounds of Examples 1, 8,275, 280, 282, 283, 284, and 293 showed EC₅₀ values of from 1 to 10 nM;and compounds of Examples 4, 36, 40, 277, 285, 286, 298, and 299 showedEC₅₀ values of from 10 nM to 1 μM.

When tested using genotype 1b wild-type transient replicon assays,compounds of Examples 1, 2, 4, 5, 6, 8, 275, 276, 281, 282, 283, 284,285, 286, 287, 288, 289, 291, 292, 293, 294, 295, 296, and 297 showedEC₅₀ values of less than 1 nM; and compounds of Examples 34, 36, 40,277, 280, 298, and 299 showed EC₅₀ values of from 1 to 10 nM.

When tested using genotype 1b R₁₅₅K transient replicon assays, compoundsof Examples 1, 2, 4, 5, 6, and 8 showed EC₅₀ values of less than 1 nM;and compounds of Examples 34, 36, 40, 298, and 299 showed EC₅₀ values offrom 1 to 10 nM.

When tested using genotype 1b D168V transient replicon assays, compoundsof Examples 1, 5, 6, 275, 276, and 282 showed EC₅₀ values of less than 1nM; and compounds of Examples 2, 4, 8, 34, 36, 40, 280, 298, and 299showed EC₅₀ values of from 1 to 100 nM.

When tested using genotype 3a wild-type stable replicon assays,compounds of Examples 1, 2, 5, 6, 275, 276, 280, 287, 288, 289, 290,291, 294, and 296 showed EC₅₀ values of less than 10 nM; compounds ofExamples 281, 282, 283, 284, 292, 293, 295, and 297 showed EC₅₀ valuesof from 10 to 100 nM; and compounds of Examples 273, 274, 277, 278, and279 showed EC₅₀ values of from 100 nM to 1 μM.

When tested using genotype 3a wild-type transient replicon assays,compounds of Examples 2, 5, 6, 275, 276, 280, 283, 289, and 291 showedEC₅₀ values of less than 10 nM; compounds of Examples 1, 4, 8, 281, 282,284, 285, and 293 showed EC₅₀ values of from 10 to 100 nM; and compoundsof Examples 65, 90, 277, and 286 showed EC₅₀ values of from 100 nM to 1μM.

When tested using genotype 3a A166T transient replicon assays, compoundsof Examples 2, 5, and 6 showed EC₅₀ values of less than 100 nM; andcompounds of Examples 1, 4, and 8 showed EC₅₀ values of from 100 to 500nM.

When tested using genotype 3a Q168R transient replicon assays, compoundsof Examples 5, 6, 275, 276, 280, 281, 282, 283, 289, 291, and 293 showedEC₅₀ values of less than 100 nM; and compounds of Examples 1, 2, 4, 8,90, 277, 284, 285, and 286 showed EC₅₀ values of from 100 nM to 1 μM.

When tested using genotype 3a S138T transient replicon assays, compoundsof Examples 5 and 6 showed EC₅₀ values of less than 100 nM; andcompounds of Examples 1, 2, 4, 8, and 65 showed EC₅₀ values of from 100nM to 1 μM.

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1-26. (canceled)
 27. A compound selected from the group consisting of:


28. The compound of claim 1, wherein the compound is:


29. The compound of claim 1, wherein the compound is:


30. The compound of claim 1, wherein the compound is: